Materiały źródłowe

• #1 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. […] Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. […] NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. […] The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. […] Fc receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability.

• #2 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. […] The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. […] The pathogenesis of DENV infection is attributed to the complex interplay between the virus, host genes, and host immune response, with the host immune response critically involved in the pathogenesis of DENV infection. In fact, DENV infection manifests as the severe form of the disease when the infection is being eliminated by the host immune response and is not correlative with peak viral load.

• #3 Dengue Virus Pathogenesis: an Integrated View

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2772360/

  Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. […] More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. […] A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease. […] The tropism of DENV for cells of the respective systems, the corresponding pathological effects of DENV infection of these systems, and the relevance of these events for the overall pathogenesis of DENV infection will be described.

• #4

  https://journals.lww.com/aptb/fulltext/2023/13080/recent_advances_on_pathogenesis,_diagnosis,.1.aspx

  Dengue is a vector-borne disease caused by the dengue virus (DENV) of family Flaviviridae. […] In recent years, substantial progress has been made in understanding various aspects of dengue, including its pathogenesis, diagnosis, prevention strategies, immunological responses, and the role of vectors in its transmission. […] The pathogenesis of DENV infection is complex and not fully understood, involving interactions between the virus, host genes, and host immune responses. Certain factors such as comorbid conditions, gender, age, body mass index, genetic polymorphisms, and previous DENV-1 infection increase the likelihood of developing severe DHF and DSS. Severe DHF is characterized by abnormal blood coagulation, plasma leakage, and increased vascular fragility. The virus also enhances capillary permeability, resulting in fluid loss, hypovolemic shock, and organ failure in DSS.

• #5 Dengue virus infection: Pathogenesis – UpToDate

  https://www.uptodate.com/contents/dengue-virus-infection-pathogenesis

  Substantial gaps remain in the comprehensive understanding of the pathogenesis of dengue virus (DENV) infections. In large part, this limitation is related to the lack of a suitable animal model of disease. Rhesus monkeys develop RNAemia and viremia similar in a pattern to humans after DENV challenge but do not develop clinical disease. Careful epidemiologic and experimental challenge studies in humans have provided valuable information on DENV infection, but detailed data on virus distribution in vivo are available only from small numbers of patients with more severe disease, unusual manifestations, or the later stages of infection. Little pathogenetic information is available concerning milder infections, which constitute the vast majority of cases. […] DENVs are members of the family Flaviviridae genus Orthoflavivirus. They are small, enveloped viruses containing a single-strand ribonucleic acid (RNA) genome of positive polarity. DENVs infect a wide range of human and nonhuman cell types in vitro. Viral replication involves the following steps: Attachment to the cell surface, Entry into the cytoplasm, Translation of viral proteins.

• #6 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. […] The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. […] The pathogenesis of DENV infection is attributed to the complex interplay between the virus, host genes, and host immune response, with the host immune response critically involved in the pathogenesis of DENV infection. In fact, DENV infection manifests as the severe form of the disease when the infection is being eliminated by the host immune response and is not correlative with peak viral load.

• #7

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. […] Dengue infection can lead to the generation of autoantibodies against DENV NS1 antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. […] Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. […] The pathogenesis of dengue virus infection and severe dengue manifestations is very complex and not completely understood. […] The pathophysiological hallmark of DHF/DSS is plasma leakage and deranged hemostasis. […] The statement that the human immune response plays a key role in the pathogenesis of the disease is favored by the fact that DENV infection displays the most severe form when the virus is being cleared by the host immune system and not with the peak viral load.

• #8 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The severe dengue manifestations in humans are mainly ascribed to the synergistic effect of all the above-mentioned factors. […] Dengue virus genome encodes for three structural proteins (C, prM (M), and E) and seven non-structural (NS) proteins (NS1, NS2a, NS2B, NS3, NS4a, NS4B, and NS5). […] The most important non-structural protein which has been implicated in the pathogenesis of dengue viral infections is NS1. […] During the acute phase of the disease, the levels of s-NS1 are particularly high, which correlates with the disease severity. […] DENV NS1 antigen was observed to be a major factor causing disruption of endothelial cell monolayer integrity as this protein has a direct action on vascular endothelium. […] Dengue NS1 can cause disruption of endothelial cell monolayer integrity by eliciting inflammatory cytokine production due to activation of macrophages and human peripheral blood mononuclear cells (PBMCs) through Toll-like receptor 4 (TLR 4).

• #9 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The severe dengue manifestations in humans are mainly ascribed to the synergistic effect of all the above-mentioned factors. […] Dengue virus genome encodes for three structural proteins (C, prM (M), and E) and seven non-structural (NS) proteins (NS1, NS2a, NS2B, NS3, NS4a, NS4B, and NS5). […] The most important non-structural protein which has been implicated in the pathogenesis of dengue viral infections is NS1. […] During the acute phase of the disease, the levels of s-NS1 are particularly high, which correlates with the disease severity. […] DENV NS1 antigen was observed to be a major factor causing disruption of endothelial cell monolayer integrity as this protein has a direct action on vascular endothelium. […] Dengue NS1 can cause disruption of endothelial cell monolayer integrity by eliciting inflammatory cytokine production due to activation of macrophages and human peripheral blood mononuclear cells (PBMCs) through Toll-like receptor 4 (TLR 4).

• #10 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The severe dengue manifestations in humans are mainly ascribed to the synergistic effect of all the above-mentioned factors. […] Dengue virus genome encodes for three structural proteins (C, prM (M), and E) and seven non-structural (NS) proteins (NS1, NS2a, NS2B, NS3, NS4a, NS4B, and NS5). […] The most important non-structural protein which has been implicated in the pathogenesis of dengue viral infections is NS1. […] During the acute phase of the disease, the levels of s-NS1 are particularly high, which correlates with the disease severity. […] DENV NS1 antigen was observed to be a major factor causing disruption of endothelial cell monolayer integrity as this protein has a direct action on vascular endothelium. […] Dengue NS1 can cause disruption of endothelial cell monolayer integrity by eliciting inflammatory cytokine production due to activation of macrophages and human peripheral blood mononuclear cells (PBMCs) through Toll-like receptor 4 (TLR 4).

• #11

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  DENV NS1 antigen was observed to be a major factor causing disruption of endothelial cell monolayer integrity as this protein has a direct action on vascular endothelium. […] Dengue NS1 can cause disruption of endothelial cell monolayer integrity by eliciting inflammatory cytokine production due to activation of macrophages and human peripheral blood mononuclear cells (PBMCs) through Toll-like receptor 4 (TLR 4). […] It has been observed in mouse model experiments that the endothelial permeability was increased by DENV NS1 in a dose-dependent manner. […] Moreover, endothelial permeability returned to normal after administration of anti-NS1 antibodies. […] NS1 also induces shedding of heparan sulfate proteoglycans, which leads to the disruption of the endothelial glycocalyx layer in human pulmonary vascular endothelial cells and resulted in loss of sialic acid from cell surface.

• #12 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The severe dengue manifestations in humans are mainly ascribed to the synergistic effect of all the above-mentioned factors. […] Dengue virus genome encodes for three structural proteins (C, prM (M), and E) and seven non-structural (NS) proteins (NS1, NS2a, NS2B, NS3, NS4a, NS4B, and NS5). […] The most important non-structural protein which has been implicated in the pathogenesis of dengue viral infections is NS1. […] During the acute phase of the disease, the levels of s-NS1 are particularly high, which correlates with the disease severity. […] DENV NS1 antigen was observed to be a major factor causing disruption of endothelial cell monolayer integrity as this protein has a direct action on vascular endothelium. […] Dengue NS1 can cause disruption of endothelial cell monolayer integrity by eliciting inflammatory cytokine production due to activation of macrophages and human peripheral blood mononuclear cells (PBMCs) through Toll-like receptor 4 (TLR 4).

• #13 Dengue virus pathogenesis and host molecular machineries | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01030-9

  Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation. […] The NS1 protein has multiple roles inside and outside the host cell; it also serves as an early indicator to diagnose and assess the level of DENV infection. NS1 plays a vital role in severe dengue physiopathology, specifically plasma leakage. A recent report suggested that NS1 activates macrophages via Toll-like receptor 4 (TLR4) and disrupts endothelial cells, resulting in vascular leakage.

• #14 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  It has been observed in mouse model experiments that the endothelial permeability was increased by DENV NS1 in a dose-dependent manner. […] Moreover, endothelial permeability returned to normal after administration of anti-NS1 antibodies. […] NS1 also induces shedding of heparan sulfate proteoglycans, which leads to the disruption of the endothelial glycocalyx layer in human pulmonary vascular endothelial cells and resulted in loss of sialic acid from cell surface. […] All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

• #15 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  It has been observed in mouse model experiments that the endothelial permeability was increased by DENV NS1 in a dose-dependent manner. […] Moreover, endothelial permeability returned to normal after administration of anti-NS1 antibodies. […] NS1 also induces shedding of heparan sulfate proteoglycans, which leads to the disruption of the endothelial glycocalyx layer in human pulmonary vascular endothelial cells and resulted in loss of sialic acid from cell surface. […] All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

• #16 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  It has been observed in mouse model experiments that the endothelial permeability was increased by DENV NS1 in a dose-dependent manner. […] Moreover, endothelial permeability returned to normal after administration of anti-NS1 antibodies. […] NS1 also induces shedding of heparan sulfate proteoglycans, which leads to the disruption of the endothelial glycocalyx layer in human pulmonary vascular endothelial cells and resulted in loss of sialic acid from cell surface. […] All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

• #17

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines. […] This subsequently leads to plasma leakage and accumulation of fluid in third space, ultimately causing dengue shock syndrome. […] A major factor that is considered responsible for severe dengue pathogenesis is disorganized release of cytokines. […] The importance of the role played by anti-NS1 antibody mediated immune response in the development of manifestations of severe dengue cannot be undermined.

• #18 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  It has been observed in mouse model experiments that the endothelial permeability was increased by DENV NS1 in a dose-dependent manner. […] Moreover, endothelial permeability returned to normal after administration of anti-NS1 antibodies. […] NS1 also induces shedding of heparan sulfate proteoglycans, which leads to the disruption of the endothelial glycocalyx layer in human pulmonary vascular endothelial cells and resulted in loss of sialic acid from cell surface. […] All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

• #19

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines. […] This subsequently leads to plasma leakage and accumulation of fluid in third space, ultimately causing dengue shock syndrome. […] A major factor that is considered responsible for severe dengue pathogenesis is disorganized release of cytokines. […] The importance of the role played by anti-NS1 antibody mediated immune response in the development of manifestations of severe dengue cannot be undermined.

• #20

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines. […] This subsequently leads to plasma leakage and accumulation of fluid in third space, ultimately causing dengue shock syndrome. […] A major factor that is considered responsible for severe dengue pathogenesis is disorganized release of cytokines. […] The importance of the role played by anti-NS1 antibody mediated immune response in the development of manifestations of severe dengue cannot be undermined.

• #21 Dengue virus pathogenesis and host molecular machineries | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01030-9

  The importance of the NS3 protein for the survival of the virus makes it a target for antiviral drugs. NS4B interacts with NS3 to modulate viral infection, while NS4A indirectly assists in the viral replication process by inducing autophagy, preventing cell death, which is beneficial for viral replication. […] Whenever the dengue virus infects the human host, both the innate (interferons, complement system, etc.) and adaptive (immunoglobulins and cytotoxic T-cells) immune systems are stimulated to neutralize the virus. In severe Dengue infection, the uncontrolled generation of inflammatory cytokines, leading to a phenomenon termed cytokine storm, has been principally implicated as the causal agent of fatality. […] Addressing the various host-viral modifications at the molecular level may provide key insights into viral evolution, viral escape mechanisms, host-virus interactions, disease consequences, and public health readiness.

• #22 Dengue virus pathogenesis and host molecular machineries | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01030-9

  The genome of the Dengue virus initiates the formation of a single polypeptide through translation, subsequently processed to yield various functional and non-functional proteins. These proteins undergo post-translational modifications. […] During infection, these modifications can exert either proviral or antiviral effects by activating or inhibiting proteins or modulating the immune response. An example is the TRIM family protein TRIM69, an interferon-stimulated gene (ISG). […] DENV NS5 associates with Signal Transducer and Activator of Transcription 2 (STAT2), a critical component in interferon signaling, preventing its phosphorylation and targeting it for proteasomal degradation.

• #23 Dengue virus pathogenesis and host molecular machineries | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01030-9

  Modulation of epigenetic regulation in the host-DENV interaction is not yet completely understood. Recent years have seen growing evidence highlighting the pivotal role of epigenetic regulators in gene expression regulation. […] This epigenetic modification is important for investigating mental health issues related to dengue infection. […] The role of m6A methylation has been implicated in potentially regulating these genes/lncRNAs to enhance DENV replication. […] DENV exhibits distinct characteristics among its four serotypes, with DENV2, in particular, showcasing a reliance on increased glucose utilization and enhanced glucose metabolism to produce the necessary metabolic intermediates essential for viral replication. […] The dengue virus NS5 protein intrudes in the cellular spliceosome and modulates splicing.

• #24 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. […] Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. […] NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. […] The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. […] Fc receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability.

• #25 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  Moreover, antibody-dependent enhancement (ADE) upon infection also contributes to pathogenesis and virulence of the disease. […] The phenomenon of ADE contributes to the severe form of the disease and could be itself classified as a type of immunopathology. […] The presence of diverse HLA-restricted T-cell epitopes on different proteins is seen in individuals who are immune to DENV infection. […] DENV-specific antibodies perform a wide range of functions. These antibodies clear the infection through various mechanisms including restraining the viral binding to cell surface receptors or by inhibiting viral infusion after binding. […] The phenomenon of extrinsic ADE occurs externally to mononuclear phagocytes and involves an increased rate of receptor interaction and internalization of the virus–immune complex.

• #26 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The phenomenon of antibody-dependent enhancement is not only seen in dengue virus infection, but it has also been found to be associated with several other viral infections such as influenza, enteroviruses, etc. […] A subsequent heterotypic dengue infection after a primary infection may lead to the cross-reactive non-neutralizing pre-existing antibodies binding to the virus but not being able to neutralize it, thus forming virion-antibody immune complexes. […] This increase in viral load starts an immunopathogenic cascade, ultimately leading to vascular leak and manifestations of severe dengue infection. […] The role of immune regulatory mechanisms of the immune system, which are CD4+ FoxP3 expressing regulatory T cells (Tregs), has also been investigated by some researchers. […] A balance between Th1 and Th2 is important for the control of immune response to microorganisms.

• #27 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  Dengue virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. […] The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fc receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. […] When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito’s saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells. The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.

• #28 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  Dengue virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. […] The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fc receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. […] When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito’s saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells. The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.

• #29 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The phenomenon of antibody-dependent enhancement is not only seen in dengue virus infection, but it has also been found to be associated with several other viral infections such as influenza, enteroviruses, etc. […] A subsequent heterotypic dengue infection after a primary infection may lead to the cross-reactive non-neutralizing pre-existing antibodies binding to the virus but not being able to neutralize it, thus forming virion-antibody immune complexes. […] This increase in viral load starts an immunopathogenic cascade, ultimately leading to vascular leak and manifestations of severe dengue infection. […] The role of immune regulatory mechanisms of the immune system, which are CD4+ FoxP3 expressing regulatory T cells (Tregs), has also been investigated by some researchers. […] A balance between Th1 and Th2 is important for the control of immune response to microorganisms.

• #30 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. […] Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. […] NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. […] The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. […] Fc receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability.

• #31 Dengue: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/215840-overview

  This results in increased viral entry into macrophages bearing IgG receptors, allowing unchecked viral replication with higher viral titers and increased cytokine production and complement activation, a phenomenon called antibody-dependent enhancement. […] The affected macrophages release vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock.

• #32 Dengue virus pathogenesis and host molecular machineries | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01030-9

  The importance of the NS3 protein for the survival of the virus makes it a target for antiviral drugs. NS4B interacts with NS3 to modulate viral infection, while NS4A indirectly assists in the viral replication process by inducing autophagy, preventing cell death, which is beneficial for viral replication. […] Whenever the dengue virus infects the human host, both the innate (interferons, complement system, etc.) and adaptive (immunoglobulins and cytotoxic T-cells) immune systems are stimulated to neutralize the virus. In severe Dengue infection, the uncontrolled generation of inflammatory cytokines, leading to a phenomenon termed cytokine storm, has been principally implicated as the causal agent of fatality. […] Addressing the various host-viral modifications at the molecular level may provide key insights into viral evolution, viral escape mechanisms, host-virus interactions, disease consequences, and public health readiness.

• #33

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  All these factors contributed to the increase in vascular permeability by direct action of NS1 antigen. […] Meanwhile, NS1-mediated release of inflammatory cytokines from immune cells also contributes to endothelial hyperpermeability and vascular leak. […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines. […] This subsequently leads to plasma leakage and accumulation of fluid in third space, ultimately causing dengue shock syndrome. […] A major factor that is considered responsible for severe dengue pathogenesis is disorganized release of cytokines. […] The importance of the role played by anti-NS1 antibody mediated immune response in the development of manifestations of severe dengue cannot be undermined.

• #34 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  During DENV infection, most of the immune cells, including monocytes, macrophages, NK, invariant natural killer cells (iNKT), and DENV-specific CD4 and CD8 T cells, secrete huge amounts of TNF-α that contribute to inflammation and enhanced vascular permeability. […] The cytokine profile varies during dengue infection and further disease progression. […] The presence of DENV antigens such as E protein and NS3 have been detected in different tissues, including skin, liver, spleen, lymph node, kidney, bone marrow, lungs, thymus, and brain. […] DENV can infect several types of parenchymal and nonparenchymal cells, including epithelial and endothelial cells, hepatocytes, muscle cells, DCs, monocytes, macrophages, mast cells, and B and T cells. […] The release of exosomes from DENV infected cell line C6/36 has been reported.

• #35 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  During DENV infection, most of the immune cells, including monocytes, macrophages, NK, invariant natural killer cells (iNKT), and DENV-specific CD4 and CD8 T cells, secrete huge amounts of TNF-α that contribute to inflammation and enhanced vascular permeability. […] The cytokine profile varies during dengue infection and further disease progression. […] The presence of DENV antigens such as E protein and NS3 have been detected in different tissues, including skin, liver, spleen, lymph node, kidney, bone marrow, lungs, thymus, and brain. […] DENV can infect several types of parenchymal and nonparenchymal cells, including epithelial and endothelial cells, hepatocytes, muscle cells, DCs, monocytes, macrophages, mast cells, and B and T cells. […] The release of exosomes from DENV infected cell line C6/36 has been reported.

• #36 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  The pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. […] Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. […] NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. […] The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. […] Fc receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability.

• #37 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. […] Dengue infection can lead to the generation of autoantibodies against DENV NS1 antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. […] Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. […] The pathogenesis of dengue virus infection and severe dengue manifestations is very complex and not completely understood. […] The pathogenesis of dengue was attributed to various viral and host factors such as non-structural protein 1 (NS1) viral antigen, DENV genome variation, subgenomic RNA, antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies and autoimmunity.

• #38

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. […] Dengue infection can lead to the generation of autoantibodies against DENV NS1 antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. […] Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. […] The pathogenesis of dengue virus infection and severe dengue manifestations is very complex and not completely understood. […] The pathophysiological hallmark of DHF/DSS is plasma leakage and deranged hemostasis. […] The statement that the human immune response plays a key role in the pathogenesis of the disease is favored by the fact that DENV infection displays the most severe form when the virus is being cleared by the host immune system and not with the peak viral load.

• #39 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  This subsequently leads to plasma leakage and accumulation of fluid in third space, ultimately causing dengue shock syndrome. […] A major factor that is considered responsible for severe dengue pathogenesis is disorganized release of cytokines. […] Several cytokines and chemokines are secreted by the human endothelial cells, in response to anti-DENV NS1 antibodies. […] The importance of the role played by anti-NS1 antibody mediated immune response in the development of manifestations of severe dengue cannot be undermined. […] It has been observed that serum AST and ALT levels were much higher in mice administered anti-DENV NS1 IgG. […] Anti-DENV NS1 antibodies might also have a role to play in liver damage. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections.

• #40

  https://link.springer.com/article/10.1007/s00203-024-03954-0

  A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. […] Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. […] Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. […] This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis.

• #41

  https://link.springer.com/article/10.1007/s00203-024-03954-0

  A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. […] Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. […] Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. […] This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis.

• #42

  https://link.springer.com/article/10.1007/s00203-024-03954-0

  Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. […] Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV.

• #43 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: Part I – Dengue Virus Tropism, Host Innate Immune Responses, and Subversion of Antiviral Responses | IntechOpen

  https://www.intechopen.com/chapters/73195

  The NS1 protein of DENV and other related flaviviruses has been described as an essential cofactor in virus replication and assembly. […] Interestingly, the secreted form of NS1 is also implicated in immune evasion strategies via interaction with several proteins of the complement pathways that protect the virus-infected cells from the immune system processing. […] Additionally, the soluble NS1 from DENV can interact with the surface of endothelial cells, immune cells, and platelets to cause endothelial barrier dysfunction and vascular leakage, and potentially hampers the coagulation cascades leading to hemorrhagic manifestations during DENV infection. […] The hallmark of severe dengue is the transient perturbation in the integrity of the endothelium lining the inner side of blood vessels as well as the alteration in the coagulation cascade leading to shock and severe hemorrhage manifestations.

• #44 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: Part I – Dengue Virus Tropism, Host Innate Immune Responses, and Subversion of Antiviral Responses | IntechOpen

  https://www.intechopen.com/chapters/73195

  Increased vascular permeability in severe dengue results in decreased circulating plasma volume, haemoconcentration, and pleural and peritoneal effusions that result in severe life-threatening shock. […] Although many severe infections occur upon secondary encounters with heterologous DENV serotypes, suggesting an immune-mediated process is involved, the multifactorial immunopathogenic process of DENV infection implies a complex interaction between distinct viral and host processes that sometimes leads to increased virus infection, exacerbated immune responses, and the appearance of life-threatening severe manifestations such as severe plasma leakage, hemorrhage, and organ failure. […] Higher virus pathogenicity (virulence), preexisting serotype cross-reactive antibodies, activation of DENV-infected immune cells, T cell responses, activation of complement pathways, the potential infection of endothelial cells, and the new pathogenic roles of the secreted NS1 of DENV may work synergistically to induce the release of vasoactive cytokines which results in increased endothelial permeability causing vascular leakage and pleural effusion, which are still considered pathognomonic features of severe dengue that leads occasionally to shock and death.

• #45 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  The term cytokine storm is referred to the exacerbated and unbalanced production of cytokines and chemokines which exert many effector functions including antiviral response and inflammation. […] The homeostasis of the endothelial barrier is mainly maintained by two structures: a) the endothelial glycocalyx layer (EGL), a network of membrane-bound glycosaminoglycans (e.g heparan sulfate [HS], hyaluronic acid [HA], chondroitin sulfate [CS]) and proteoglycans (e.g syndecan-1, perlecan, glypicans), covering the endothelium luminally and playing critical roles in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell-vessel wall interactions; and b) the intercellular junction complex (IJC), mainly composed of the tight (e.g. ZO-1, occluding, claudins) and adherens (e.g. VE-cadherin, beta-catenin) junction proteins that maintain the cell-to-cell contacts to control fluids and small molecules exchange between the luminal side (bloodstream) and the abluminal side (tissues compartment) of blood vessels.

• #46 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  The disruption of any of these two main components under pathological conditions leads to increased inflammatory responses with pathogenic consequences involving barrier dysfunction and vascular disorders that result in excessive extravasation of fluids and proteins into the tissues, hypotension, shock, and sometimes, death. […] In addition to modulating the endothelial barrier function, cytokine and chemokines secreted by DENV infected cells pose important effector functions that promote the recruitment and activation of other immune cells such as NK cells with the ability to induce apoptosis of susceptible target cells (e.g. DENV infected cells) via NK cell-mediated cytotoxicity, and antibody (Ab)-dependent NK cell-mediated cytotoxicity (ADCC). […] The release of cytotoxic granules and cytokines by NK cells may also contribute to a cytokine storm, and the tissue damage associated with infection clearance may exacerbate the pro-inflammatory environment.

• #47 Dengue Virus Pathogenesis: an Integrated View

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2772360/

  DENV has also been shown to have tropism for circulating mononuclear cells in blood and for cells residing in the spleen, lymph nodes, and bone marrow of infected AG129 mice. […] Understanding the mechanism underlying the development of shock is crucial for the development of novel strategies to improve patient management. […] It is worth noting that patients classified as having DHF and DSS have no generalized edema; rather, a selective plasma leakage tends to occur in the pleural and abdominal cavities. […] Attempts to explain the pathogenesis of dengue in all its complexity must consider all the clinical, immunological, pathological, and epidemiological features of DENV infection. […] The mechanisms leading to the severe manifestations of DENV infections are still not completely understood but are likely to be multifactorial.

• #48 Dengue: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/215840-overview

  Dengue fever is a mosquito-borne viral disease caused by 1 of 4 closely related but antigenically distinct serotypes of dengue virus, serotypes DENV-1 through DEN-4. […] Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, macrophages, hepatocytes, and endothelial cells, result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections. […] Severe dengue (dengue hemorrhagic fever/dengue shock syndrome) usually occur around the third to seventh day of illness during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype. […] The critical feature of severe dengue is plasma leakage. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites.

• #49 Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

  https://www.mdpi.com/1999-4915/16/7/1090

  Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. A dysregulated host immune response, including antibody-dependent enhancement (ADE), is thought to drive most of the complications associated with severe dengue, in particular the haematologic manifestations. Haematologic abnormalities are a key feature of dengue, with coagulopathy, thrombocytopaenia and leucocyte abnormalities being well described. The specific mechanism underlying coagulation abnormalities associated with dengue remains unclear. Various pathogenic mechanisms have been proposed. The NS1 protein can bind to both thrombin and prothrombin. While binding to thrombin has no effects, it inhibits the activation of prothrombin. NS1 also mediates the activation of plasminogen via plasminogen cross-reactive antibodies, thereby enhancing fibrinolytic activity and bleeding. DENV-induced hepatocellular injury also contributes to coagulopathy via reduced synthesis of coagulation factors and may at least partly explain the prolongation of both aPTT and PT. An imbalance between coagulation and fibrinolysis is also postulated to cause haemorrhagic complications in DHS and DSS. DENV-induced macrophage migration inhibitory factor promotes bleeding by inducing platelet-activating factor. Furthermore, increased IL-6 downregulates the production of factor XII, which initiates the intrinsic coagulation pathway, resulting in prolongation of the aPTT. Excessive tissue plasminogen activator (tPA) production in DHS/DSS leads to hyperfibrinolysis and further exacerbates the bleeding tendency. Indeed, dengue patients with bleeding complications were shown to have higher levels of tPA, D-dimer and reduced thrombin formation compared to those without bleeding. Similar results were demonstrated in children with DHF, where von Willebrand factor antigen (vWF: Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were increased, but ADAMTS-13 (a dis-integrin and metalloprotease with thrombospondin repeats) was significantly reduced. It is likely that the rises in vWF: Ag, TF and PAI-1 are a response to the acute inflammatory state in DHF, and the concomitant rise in tPA and consumption of coagulation factors tips the balance in favour of bleeding. Furthermore, excessive vWF may lead to abnormal platelet activation and aggregation, contributing to thrombocytopaenia and bleeding. Disseminated intravascular coagulation (DIC) is also a major contributor to dengue-related coagulopathy and was recently reported to occur in 26% of patients with severe disease, in addition to being a predictive factor for early mortality. Taken together, these data suggest that reduced thrombin formation and increased fibrinolytic activity are the key contributing factors to bleeding complications in dengue infection. It is noteworthy that dengue-related coagulopathy is a result of both the direct effects of the virus on the haemostatic system as well as the dysregulated host immune response.

• #50 Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

  https://www.mdpi.com/1999-4915/16/7/1090

  Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. A dysregulated host immune response, including antibody-dependent enhancement (ADE), is thought to drive most of the complications associated with severe dengue, in particular the haematologic manifestations. Haematologic abnormalities are a key feature of dengue, with coagulopathy, thrombocytopaenia and leucocyte abnormalities being well described. The specific mechanism underlying coagulation abnormalities associated with dengue remains unclear. Various pathogenic mechanisms have been proposed. The NS1 protein can bind to both thrombin and prothrombin. While binding to thrombin has no effects, it inhibits the activation of prothrombin. NS1 also mediates the activation of plasminogen via plasminogen cross-reactive antibodies, thereby enhancing fibrinolytic activity and bleeding. DENV-induced hepatocellular injury also contributes to coagulopathy via reduced synthesis of coagulation factors and may at least partly explain the prolongation of both aPTT and PT. An imbalance between coagulation and fibrinolysis is also postulated to cause haemorrhagic complications in DHS and DSS. DENV-induced macrophage migration inhibitory factor promotes bleeding by inducing platelet-activating factor. Furthermore, increased IL-6 downregulates the production of factor XII, which initiates the intrinsic coagulation pathway, resulting in prolongation of the aPTT. Excessive tissue plasminogen activator (tPA) production in DHS/DSS leads to hyperfibrinolysis and further exacerbates the bleeding tendency. Indeed, dengue patients with bleeding complications were shown to have higher levels of tPA, D-dimer and reduced thrombin formation compared to those without bleeding. Similar results were demonstrated in children with DHF, where von Willebrand factor antigen (vWF: Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were increased, but ADAMTS-13 (a dis-integrin and metalloprotease with thrombospondin repeats) was significantly reduced. It is likely that the rises in vWF: Ag, TF and PAI-1 are a response to the acute inflammatory state in DHF, and the concomitant rise in tPA and consumption of coagulation factors tips the balance in favour of bleeding. Furthermore, excessive vWF may lead to abnormal platelet activation and aggregation, contributing to thrombocytopaenia and bleeding. Disseminated intravascular coagulation (DIC) is also a major contributor to dengue-related coagulopathy and was recently reported to occur in 26% of patients with severe disease, in addition to being a predictive factor for early mortality. Taken together, these data suggest that reduced thrombin formation and increased fibrinolytic activity are the key contributing factors to bleeding complications in dengue infection. It is noteworthy that dengue-related coagulopathy is a result of both the direct effects of the virus on the haemostatic system as well as the dysregulated host immune response.

• #51 Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

  https://www.mdpi.com/1999-4915/16/7/1090

  Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. A dysregulated host immune response, including antibody-dependent enhancement (ADE), is thought to drive most of the complications associated with severe dengue, in particular the haematologic manifestations. Haematologic abnormalities are a key feature of dengue, with coagulopathy, thrombocytopaenia and leucocyte abnormalities being well described. The specific mechanism underlying coagulation abnormalities associated with dengue remains unclear. Various pathogenic mechanisms have been proposed. The NS1 protein can bind to both thrombin and prothrombin. While binding to thrombin has no effects, it inhibits the activation of prothrombin. NS1 also mediates the activation of plasminogen via plasminogen cross-reactive antibodies, thereby enhancing fibrinolytic activity and bleeding. DENV-induced hepatocellular injury also contributes to coagulopathy via reduced synthesis of coagulation factors and may at least partly explain the prolongation of both aPTT and PT. An imbalance between coagulation and fibrinolysis is also postulated to cause haemorrhagic complications in DHS and DSS. DENV-induced macrophage migration inhibitory factor promotes bleeding by inducing platelet-activating factor. Furthermore, increased IL-6 downregulates the production of factor XII, which initiates the intrinsic coagulation pathway, resulting in prolongation of the aPTT. Excessive tissue plasminogen activator (tPA) production in DHS/DSS leads to hyperfibrinolysis and further exacerbates the bleeding tendency. Indeed, dengue patients with bleeding complications were shown to have higher levels of tPA, D-dimer and reduced thrombin formation compared to those without bleeding. Similar results were demonstrated in children with DHF, where von Willebrand factor antigen (vWF: Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were increased, but ADAMTS-13 (a dis-integrin and metalloprotease with thrombospondin repeats) was significantly reduced. It is likely that the rises in vWF: Ag, TF and PAI-1 are a response to the acute inflammatory state in DHF, and the concomitant rise in tPA and consumption of coagulation factors tips the balance in favour of bleeding. Furthermore, excessive vWF may lead to abnormal platelet activation and aggregation, contributing to thrombocytopaenia and bleeding. Disseminated intravascular coagulation (DIC) is also a major contributor to dengue-related coagulopathy and was recently reported to occur in 26% of patients with severe disease, in addition to being a predictive factor for early mortality. Taken together, these data suggest that reduced thrombin formation and increased fibrinolytic activity are the key contributing factors to bleeding complications in dengue infection. It is noteworthy that dengue-related coagulopathy is a result of both the direct effects of the virus on the haemostatic system as well as the dysregulated host immune response.

• #52 Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

  https://www.mdpi.com/1999-4915/16/7/1090

  Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. A dysregulated host immune response, including antibody-dependent enhancement (ADE), is thought to drive most of the complications associated with severe dengue, in particular the haematologic manifestations. Haematologic abnormalities are a key feature of dengue, with coagulopathy, thrombocytopaenia and leucocyte abnormalities being well described. The specific mechanism underlying coagulation abnormalities associated with dengue remains unclear. Various pathogenic mechanisms have been proposed. The NS1 protein can bind to both thrombin and prothrombin. While binding to thrombin has no effects, it inhibits the activation of prothrombin. NS1 also mediates the activation of plasminogen via plasminogen cross-reactive antibodies, thereby enhancing fibrinolytic activity and bleeding. DENV-induced hepatocellular injury also contributes to coagulopathy via reduced synthesis of coagulation factors and may at least partly explain the prolongation of both aPTT and PT. An imbalance between coagulation and fibrinolysis is also postulated to cause haemorrhagic complications in DHS and DSS. DENV-induced macrophage migration inhibitory factor promotes bleeding by inducing platelet-activating factor. Furthermore, increased IL-6 downregulates the production of factor XII, which initiates the intrinsic coagulation pathway, resulting in prolongation of the aPTT. Excessive tissue plasminogen activator (tPA) production in DHS/DSS leads to hyperfibrinolysis and further exacerbates the bleeding tendency. Indeed, dengue patients with bleeding complications were shown to have higher levels of tPA, D-dimer and reduced thrombin formation compared to those without bleeding. Similar results were demonstrated in children with DHF, where von Willebrand factor antigen (vWF: Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were increased, but ADAMTS-13 (a dis-integrin and metalloprotease with thrombospondin repeats) was significantly reduced. It is likely that the rises in vWF: Ag, TF and PAI-1 are a response to the acute inflammatory state in DHF, and the concomitant rise in tPA and consumption of coagulation factors tips the balance in favour of bleeding. Furthermore, excessive vWF may lead to abnormal platelet activation and aggregation, contributing to thrombocytopaenia and bleeding. Disseminated intravascular coagulation (DIC) is also a major contributor to dengue-related coagulopathy and was recently reported to occur in 26% of patients with severe disease, in addition to being a predictive factor for early mortality. Taken together, these data suggest that reduced thrombin formation and increased fibrinolytic activity are the key contributing factors to bleeding complications in dengue infection. It is noteworthy that dengue-related coagulopathy is a result of both the direct effects of the virus on the haemostatic system as well as the dysregulated host immune response.

• #53 Immuno-Haematologic Aspects of Dengue Infection: Biologic Insights and Clinical Implications

  https://www.mdpi.com/1999-4915/16/7/1090

  Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. A dysregulated host immune response, including antibody-dependent enhancement (ADE), is thought to drive most of the complications associated with severe dengue, in particular the haematologic manifestations. Haematologic abnormalities are a key feature of dengue, with coagulopathy, thrombocytopaenia and leucocyte abnormalities being well described. The specific mechanism underlying coagulation abnormalities associated with dengue remains unclear. Various pathogenic mechanisms have been proposed. The NS1 protein can bind to both thrombin and prothrombin. While binding to thrombin has no effects, it inhibits the activation of prothrombin. NS1 also mediates the activation of plasminogen via plasminogen cross-reactive antibodies, thereby enhancing fibrinolytic activity and bleeding. DENV-induced hepatocellular injury also contributes to coagulopathy via reduced synthesis of coagulation factors and may at least partly explain the prolongation of both aPTT and PT. An imbalance between coagulation and fibrinolysis is also postulated to cause haemorrhagic complications in DHS and DSS. DENV-induced macrophage migration inhibitory factor promotes bleeding by inducing platelet-activating factor. Furthermore, increased IL-6 downregulates the production of factor XII, which initiates the intrinsic coagulation pathway, resulting in prolongation of the aPTT. Excessive tissue plasminogen activator (tPA) production in DHS/DSS leads to hyperfibrinolysis and further exacerbates the bleeding tendency. Indeed, dengue patients with bleeding complications were shown to have higher levels of tPA, D-dimer and reduced thrombin formation compared to those without bleeding. Similar results were demonstrated in children with DHF, where von Willebrand factor antigen (vWF: Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were increased, but ADAMTS-13 (a dis-integrin and metalloprotease with thrombospondin repeats) was significantly reduced. It is likely that the rises in vWF: Ag, TF and PAI-1 are a response to the acute inflammatory state in DHF, and the concomitant rise in tPA and consumption of coagulation factors tips the balance in favour of bleeding. Furthermore, excessive vWF may lead to abnormal platelet activation and aggregation, contributing to thrombocytopaenia and bleeding. Disseminated intravascular coagulation (DIC) is also a major contributor to dengue-related coagulopathy and was recently reported to occur in 26% of patients with severe disease, in addition to being a predictive factor for early mortality. Taken together, these data suggest that reduced thrombin formation and increased fibrinolytic activity are the key contributing factors to bleeding complications in dengue infection. It is noteworthy that dengue-related coagulopathy is a result of both the direct effects of the virus on the haemostatic system as well as the dysregulated host immune response.

• #54 Thrombocytopenia in dengue infection: mechanisms and a potential application | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/thrombocytopenia-in-dengue-infection-mechanisms-and-a-potential-application/E7CF2A05E263413F71587B8BCA881844

  Thrombocytopenia is a common symptom and one of the warning signs of dengue virus (DENV) infection. Platelet depletion is critical as it may lead to other severe dengue symptoms. Understanding the molecular events of this condition during dengue infection is challenging because of the multifaceted factors involved in DENV infection and the dynamics of the disease progression. Platelet levels depend on the balance between platelet production and platelet consumption or clearance. Megakaryopoiesis and thrombopoiesis, two interdependent processes in platelet production, are hampered during dengue infection. Conversely, platelet elimination via platelet activation, apoptosis and clearance processes are elevated. Together, these anomalies contribute to thrombocytopenia in dengue patients. Targeting the molecular events of dengue-mediated thrombocytopenia shows great potential but still requires further investigation.

• #55 Thrombocytopenia in dengue infection: mechanisms and a potential application | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/thrombocytopenia-in-dengue-infection-mechanisms-and-a-potential-application/E7CF2A05E263413F71587B8BCA881844

  The mechanisms of dengue-mediated thrombocytopenia in patients still eluded researchers, but significant progress has been made in recent years. In short, dengue infection may disrupt platelet production in the bone marrow and/or expedite platelet clearance, causing thrombocytopenia. […] DENV causes platelet reduction in patients, beginning typically on day 2 before the onset of the critical phase and persisting until days 67. One mechanism of thrombocytopenia is megakaryocyte infection and death. DENV has been shown to efficiently infect human megakaryocyte cell lines, primary human megakaryocytes or progenitors and megakaryocytes in humanized mice. […] In addition to impaired megakaryopoiesis, DENV infection can hamper thrombopoiesis by significantly reducing proplatelet formation in PMA-treated MEG-01 cells. The exact mechanism of this effect is currently unclear but may involve the NF-E2 transcription factor, a crucial thrombopoiesis factor. DENV infection markedly reduced NF-E2 protein expression in mature MEG-01 cells.

• #56 Thrombocytopenia in dengue infection: mechanisms and a potential application | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/thrombocytopenia-in-dengue-infection-mechanisms-and-a-potential-application/E7CF2A05E263413F71587B8BCA881844

  The mechanisms of dengue-mediated thrombocytopenia in patients still eluded researchers, but significant progress has been made in recent years. In short, dengue infection may disrupt platelet production in the bone marrow and/or expedite platelet clearance, causing thrombocytopenia. […] DENV causes platelet reduction in patients, beginning typically on day 2 before the onset of the critical phase and persisting until days 67. One mechanism of thrombocytopenia is megakaryocyte infection and death. DENV has been shown to efficiently infect human megakaryocyte cell lines, primary human megakaryocytes or progenitors and megakaryocytes in humanized mice. […] In addition to impaired megakaryopoiesis, DENV infection can hamper thrombopoiesis by significantly reducing proplatelet formation in PMA-treated MEG-01 cells. The exact mechanism of this effect is currently unclear but may involve the NF-E2 transcription factor, a crucial thrombopoiesis factor. DENV infection markedly reduced NF-E2 protein expression in mature MEG-01 cells.

• #57 Thrombocytopenia in dengue infection: mechanisms and a potential application | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/thrombocytopenia-in-dengue-infection-mechanisms-and-a-potential-application/E7CF2A05E263413F71587B8BCA881844

  The mechanisms of dengue-mediated thrombocytopenia in patients still eluded researchers, but significant progress has been made in recent years. In short, dengue infection may disrupt platelet production in the bone marrow and/or expedite platelet clearance, causing thrombocytopenia. […] DENV causes platelet reduction in patients, beginning typically on day 2 before the onset of the critical phase and persisting until days 67. One mechanism of thrombocytopenia is megakaryocyte infection and death. DENV has been shown to efficiently infect human megakaryocyte cell lines, primary human megakaryocytes or progenitors and megakaryocytes in humanized mice. […] In addition to impaired megakaryopoiesis, DENV infection can hamper thrombopoiesis by significantly reducing proplatelet formation in PMA-treated MEG-01 cells. The exact mechanism of this effect is currently unclear but may involve the NF-E2 transcription factor, a crucial thrombopoiesis factor. DENV infection markedly reduced NF-E2 protein expression in mature MEG-01 cells.

• #58 Thrombocytopenia in dengue infection: mechanisms and a potential application | Expert Reviews in Molecular Medicine | Cambridge Core

  https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/thrombocytopenia-in-dengue-infection-mechanisms-and-a-potential-application/E7CF2A05E263413F71587B8BCA881844

  In short, DENV can infect megakaryocytes at different stages of cell maturation and impair platelet production, leading to reduced platelet formation. […] The activated and apoptotic platelets are subsequently cleared from the body in several ways. Phagocytosis of apoptotic platelets by macrophages in acute and early convalescence dengue patients was reported to be 2.53.5 times higher than the platelets from healthy controls. […] The events and processes described in the sections Dengue reduces platelet production and Dengue increases platelet activation and clearance are not mutually exclusive and may simultaneously occur to exacerbate dengue symptoms.

• #59

  https://journals.lww.com/co-infectiousdiseases/Fulltext/2013/06000/The_pathogenesis_of_dengue.11.aspx?generateEpub=Article%7Cco-infectiousdiseases:2013:06000:00011%7C%7C

  The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. Better understanding of the underlying mechanisms leading to severe dengue is crucial if we are to develop prognostic markers, novel diagnostics and therapeutics and ultimately a balanced and safe vaccine.

• #60 Dengue Virus Pathogenesis: an Integrated View

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2772360/

  DENV has also been shown to have tropism for circulating mononuclear cells in blood and for cells residing in the spleen, lymph nodes, and bone marrow of infected AG129 mice. […] Understanding the mechanism underlying the development of shock is crucial for the development of novel strategies to improve patient management. […] It is worth noting that patients classified as having DHF and DSS have no generalized edema; rather, a selective plasma leakage tends to occur in the pleural and abdominal cavities. […] Attempts to explain the pathogenesis of dengue in all its complexity must consider all the clinical, immunological, pathological, and epidemiological features of DENV infection. […] The mechanisms leading to the severe manifestations of DENV infections are still not completely understood but are likely to be multifactorial.

• #61 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #62 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #63 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #64 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #65 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #66 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #67 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  Severe disease is associated with serial infection with DENV of different serotypes. […] Despite many proposed hypotheses trying to explain it, the exact immunological mechanism leading to severe dengue disease is unknown. […] In turn, severe manifestations are believed to be a consequence of the combinations of many immunopathogenic mechanisms involving viral and host factors leading to increased pathogenesis and disease. […] Of these mechanisms, the adaptive immune response has been proposed to play a critical role in the development of severe dengue manifestations. […] This includes the effect of non-neutralizing but enhancing antibodies produced during primary infections, which results in enhanced-DENV infection of Fc–receptor-expressing cells (e.g. monocytes and macrophages) during DENV heterotypic exposure in a phenomenon called antibody-dependent enhancement (ADE); the increased activation of memory T cells during secondary infections, which has low affinity for the current infecting serotype and high affinity for a past infection with a different serotype known as the original antigenic sin; the unbalanced production of pro-inflammatory cytokines that have a direct effect on vascular endothelial cells resulting in plasma leak in a phenomenon known as cytokine storm; and the excessive activation of the complement system that causes exacerbated inflammatory responses, increasing disease severity.

• #68 Dengue Immunopathogenesis: A Crosstalk between Host and Viral Factors Leading to Disease: PART II – DENV Infection, Adaptive Immune Responses, and NS1 Pathogenesis | IntechOpen

  https://www.intechopen.com/chapters/73309

  In addition to the adaptive immune responses, a secreted viral factor known as the nonstructural protein 1 (NS1) has been recently proposed as the missing corner piece of the DENV pathogenesis influencing disease. […] This Part II of the chapter will discuss the interplay between the distinct host adaptive immune responses and viral factors that together contribute to the development of DENV pathogenesis and severe disease. […] This Part II of the dengue immunopathogenesis section will address the multifactorial immunopathogenic process of DENV infection from the perspective of the pre-existing serotype cross-reactive antibodies, the hyperactivation of DENV-infected immune cells (e.g. monocytes, mast cells) leading to increased cytokine production, the role of T cell responses, the activation of complement pathways, and the new pathogenic roles of the secreted NS1 of DENV that may act together to occasionally cause severe dengue manifestations followed by shock and potentially death.

• #69 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  Dengue virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. […] The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fc receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. […] When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito’s saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells. The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.

• #70 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  Dengue virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. […] The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fc receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. […] When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito’s saliva. The virus infects nearby skin cells called keratinocytes, as well as specialized immune cells located in the skin, called Langerhans cells. The Langerhans cells migrate to the lymph nodes, where the infection spreads to white blood cells, and reproduces inside the cells while they move throughout the body.

• #71 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  The white blood cells respond by producing several signaling proteins, such as cytokines and interferons, which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability. As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever.

• #72 Dengue fever – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_fever

  The white blood cells respond by producing several signaling proteins, such as cytokines and interferons, which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability. As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever.

• #73 Dengue Virus Pathogenesis: an Integrated View

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2772360/

  DENV has also been shown to have tropism for circulating mononuclear cells in blood and for cells residing in the spleen, lymph nodes, and bone marrow of infected AG129 mice. […] Understanding the mechanism underlying the development of shock is crucial for the development of novel strategies to improve patient management. […] It is worth noting that patients classified as having DHF and DSS have no generalized edema; rather, a selective plasma leakage tends to occur in the pleural and abdominal cavities. […] Attempts to explain the pathogenesis of dengue in all its complexity must consider all the clinical, immunological, pathological, and epidemiological features of DENV infection. […] The mechanisms leading to the severe manifestations of DENV infections are still not completely understood but are likely to be multifactorial.

• #74 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  During DENV infection, most of the immune cells, including monocytes, macrophages, NK, invariant natural killer cells (iNKT), and DENV-specific CD4 and CD8 T cells, secrete huge amounts of TNF-α that contribute to inflammation and enhanced vascular permeability. […] The cytokine profile varies during dengue infection and further disease progression. […] The presence of DENV antigens such as E protein and NS3 have been detected in different tissues, including skin, liver, spleen, lymph node, kidney, bone marrow, lungs, thymus, and brain. […] DENV can infect several types of parenchymal and nonparenchymal cells, including epithelial and endothelial cells, hepatocytes, muscle cells, DCs, monocytes, macrophages, mast cells, and B and T cells. […] The release of exosomes from DENV infected cell line C6/36 has been reported.

• #75 Immune-Mediated Pathogenesis in Dengue Virus Infection

  https://www.mdpi.com/1999-4915/14/11/2575

  During DENV infection, most of the immune cells, including monocytes, macrophages, NK, invariant natural killer cells (iNKT), and DENV-specific CD4 and CD8 T cells, secrete huge amounts of TNF-α that contribute to inflammation and enhanced vascular permeability. […] The cytokine profile varies during dengue infection and further disease progression. […] The presence of DENV antigens such as E protein and NS3 have been detected in different tissues, including skin, liver, spleen, lymph node, kidney, bone marrow, lungs, thymus, and brain. […] DENV can infect several types of parenchymal and nonparenchymal cells, including epithelial and endothelial cells, hepatocytes, muscle cells, DCs, monocytes, macrophages, mast cells, and B and T cells. […] The release of exosomes from DENV infected cell line C6/36 has been reported.

• #76

  https://www.scielo.br/j/anp/a/tDpGkQZrCJ8H9VXhr3hmJ3K/

  Dengue virus (DENV) can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The CNS damage can be a result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance (thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue virus. […] The ability of a microorganism to invade the nervous system is known as neuroinvasion. Hematological seems to be the most important route used by DENV to get into the nervous system. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] Neurovirulence can be defined as the ability of the virus to induce neurologic disease. It is important to note that neurotropism is not a synonym for neurovirulence. However, in some cases, they may be associated. […] The identification of molecular signatures associated with neurovirulence of DENV is extremely important as they can serve as molecular markers of neurovirulence.

• #77

  https://www.scielo.br/j/anp/a/tDpGkQZrCJ8H9VXhr3hmJ3K/

  Dengue virus (DENV) can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The CNS damage can be a result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance (thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue virus. […] The ability of a microorganism to invade the nervous system is known as neuroinvasion. Hematological seems to be the most important route used by DENV to get into the nervous system. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] Neurovirulence can be defined as the ability of the virus to induce neurologic disease. It is important to note that neurotropism is not a synonym for neurovirulence. However, in some cases, they may be associated. […] The identification of molecular signatures associated with neurovirulence of DENV is extremely important as they can serve as molecular markers of neurovirulence.

• #78

  https://www.scielo.br/j/anp/a/tDpGkQZrCJ8H9VXhr3hmJ3K/

  Dengue virus (DENV) can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The CNS damage can be a result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance (thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue virus. […] The ability of a microorganism to invade the nervous system is known as neuroinvasion. Hematological seems to be the most important route used by DENV to get into the nervous system. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] Neurovirulence can be defined as the ability of the virus to induce neurologic disease. It is important to note that neurotropism is not a synonym for neurovirulence. However, in some cases, they may be associated. […] The identification of molecular signatures associated with neurovirulence of DENV is extremely important as they can serve as molecular markers of neurovirulence.

• #79

  https://www.scielo.br/j/anp/a/tDpGkQZrCJ8H9VXhr3hmJ3K/

  Dengue virus (DENV) can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The CNS damage can be a result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance (thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue virus. […] The ability of a microorganism to invade the nervous system is known as neuroinvasion. Hematological seems to be the most important route used by DENV to get into the nervous system. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] Neurovirulence can be defined as the ability of the virus to induce neurologic disease. It is important to note that neurotropism is not a synonym for neurovirulence. However, in some cases, they may be associated. […] The identification of molecular signatures associated with neurovirulence of DENV is extremely important as they can serve as molecular markers of neurovirulence.

• #80

  https://www.scielo.br/j/anp/a/tDpGkQZrCJ8H9VXhr3hmJ3K/

  Dengue virus (DENV) can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The CNS damage can be a result of four distinct mechanisms: (a) metabolic imbalance; (b) hemorrhagic disturbance (thrombocytopenia); (c) post-infectious autoimmune reaction; (d) CNS infection by dengue virus. […] The ability of a microorganism to invade the nervous system is known as neuroinvasion. Hematological seems to be the most important route used by DENV to get into the nervous system. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] Neurovirulence can be defined as the ability of the virus to induce neurologic disease. It is important to note that neurotropism is not a synonym for neurovirulence. However, in some cases, they may be associated. […] The identification of molecular signatures associated with neurovirulence of DENV is extremely important as they can serve as molecular markers of neurovirulence.

• #81 Dengue Virus Pathogenesis: an Integrated View

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2772360/

  The genetic background of the host influences the way that the immune response reacts to DENV infection. […] This viral load represents an important risk factor for development of severe disease. […] Ultimately, these high levels of soluble factors, many of which still remain to be identified, induce changes in EC leading to the coagulopathy and plasma leakage characteristic of DSS.

• #82

  https://journals.lww.com/co-infectiousdiseases/Fulltext/2013/06000/The_pathogenesis_of_dengue.11.aspx?generateEpub=Article%7Cco-infectiousdiseases:2013:06000:00011%7C%7C

  Dengue is one of the most rapidly spreading vector-borne diseases in the world, with the incidence increasing 30-fold in the past 50 years. There are currently no licensed treatments or vaccines for dengue. This review covers the recent advances in our understanding of dengue pathogenesis, including host and viral determinants. […] The pathogenesis of severe dengue is thought to be immune-mediated due to the timing of the clinical manifestations and higher incidence in secondary infections with a heterologous serotype. Recent evidence has provided further information of neutralizing versus enhancing monoclonal antibodies and their target epitopes on the dengue virion, which has major implications for vaccine design. The role of T-cell immunopathology has also been advanced with recent evidence of cross-reactive high pro-inflammatory cytokine producing T cells predominating in severe dengue. Recent large genome-wide association studies have identified specific susceptibility loci associated with severe disease. Epidemiological studies have served to define certain at-risk groups and specific viral virulence factors have recently been described.

• #83 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. […] Dengue infection can lead to the generation of autoantibodies against DENV NS1 antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. […] Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. […] The pathogenesis of dengue virus infection and severe dengue manifestations is very complex and not completely understood. […] The pathogenesis of dengue was attributed to various viral and host factors such as non-structural protein 1 (NS1) viral antigen, DENV genome variation, subgenomic RNA, antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies and autoimmunity.

• #84

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. […] Dengue infection can lead to the generation of autoantibodies against DENV NS1 antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. […] Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. […] The pathogenesis of dengue virus infection and severe dengue manifestations is very complex and not completely understood. […] The pathophysiological hallmark of DHF/DSS is plasma leakage and deranged hemostasis. […] The statement that the human immune response plays a key role in the pathogenesis of the disease is favored by the fact that DENV infection displays the most severe form when the virus is being cleared by the host immune system and not with the peak viral load.

• #85 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #86 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #87 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #88 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #89 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #90 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #91 Epidemiology, biology, pathogenesis, clinical manifestations, and diagnosis of dengue virus infection, and its trend in Ethiopia: a comprehensive literature review | Tropical Medicine and Health | Full Text

  https://tropmedhealth.biomedcentral.com/articles/10.1186/s41182-023-00504-0

  DENV infection and replication require step-by-step processes in host immune cells using cellular machinery. The pathogenesis of DENV infection is complex and not fully understood though the spectrum of the pathogen severity of all serotypes ranges from mild DF to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The pathogenesis is attributed to a complex interaction of the virus, host genes, and immune responses of the host. The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak. The presence of DENV sense RNA or NS3/NS5 proteins in specific cells of tissue may indicate DENV replication, as these antigens are present when DENV replicates, whereas detection of other DENV antigens (E, prM, C, (+)-sense RNA) may indicate no active replication of DENV in cells, as they do not permit replication of DENV rather cells may non-specifically take up viral RNA and other antigens from the surroundings. The infection of the DENV to host cells such as macrophages, hepatocytes, and EC influences the hemostatic and immune responses to the virus, representing a considerable risk factor for severe illness development. The DENV infection stimulates the development of specific antibodies and cellular immune responses despite the immune response aggravating the pathogenesis. The high viral load blood, viral tropism for the EC and platelet dysfunction by severe thrombocytopenia result in a high capillary fragility to cause DHF and clinically manifested as petechiae, easy bruising, and gastrointestinal mucosal bleeding. The synergistic actions of viral serotypes and various host factors, including ADE, memory cross-reactive T cells, anti-DENV NS1 antibodies, and autoimmunity play a vital role in the severe manifestations of DF in humans. The severity of DENV increases during secondary infection of different serotypes due to the weakly neutralizing antibodies from the first infection binding to the second serotype and enhancing antibody-dependent enhancement (ADE) infection by Fc-receptor-bearing immune cells, such as monocytes and macrophages. The clinical features and severity of DF occur during the existence of factors like being a neonate or young child, female, high body mass index, genetic polymorphisms and previous infection with DENV-1 if the patient contracts DENV-2 or DENV-3, co-morbidities, such as diabetes and asthma disease. During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis.

• #92 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Dengue virus (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. […] DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. […] Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide. […] Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. […] As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative.

• #93 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Dengue virus (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. […] DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. […] Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide. […] Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. […] As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative.

• #94 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Dengue virus (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. […] DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. […] Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide. […] Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. […] As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative.

• #95 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Dengue virus (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. […] DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. […] Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide. […] Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. […] As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative.

• #96 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Dengue virus (DENV) E envelope protein binds to a cellular receptor. The exact nature of the cellular receptor has not been fully elucidated. […] DENV undergoes endocytosis. Acidification of the endosome leads to a conformational change of E, exposing a fusion peptide sequence that facilitates fusion of the envelope with the endosomal membrane, releasing the virion capsid into the cytoplasm. […] Host translational machinery (ribosomes) translates the (+)ssRNA into a single polypeptide. […] Cellular and viral proteinases cleave the polypeptide into 10 proteins (E, M, C and 7 nonstructural/enzymatic proteins) while embedded on the ER membrane. […] As soon as functional RNA-dependent RNA polymerase is synthesized, RNA replication can commence. Synthesis is asymmetrical, making 10 times more of the positive-sense strand than the negative.

• #97 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Assembly occurs on intracellular membranes, which bud into the ER (forming the envelope from the ER membrane). Subsequent budding from the ER through the Golgi and into vesicles allows maturation via posttranslational modifications, e.g. glycosylation and pH transformational rearrangements. […] Egress occurs via exocytosis. […] Some people develop more severe forms of dengue, such as dengue hemorrhagic fever. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third, or fourth time. The previous antibodies to the old strain of Dengue virus now interfere with the immune response to the current strain, paradoxically leading to more virus entry and uptake.

• #98 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  Assembly occurs on intracellular membranes, which bud into the ER (forming the envelope from the ER membrane). Subsequent budding from the ER through the Golgi and into vesicles allows maturation via posttranslational modifications, e.g. glycosylation and pH transformational rearrangements. […] Egress occurs via exocytosis. […] Some people develop more severe forms of dengue, such as dengue hemorrhagic fever. Different strains of viruses interacting with people with different immune backgrounds lead to a complex interaction. Among the possible causes are cross-serotypic immune response, through a mechanism known as antibody-dependent enhancement, which happens when a person who has been previously infected with dengue gets infected for the second, third, or fourth time. The previous antibodies to the old strain of Dengue virus now interfere with the immune response to the current strain, paradoxically leading to more virus entry and uptake.

• #99 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  In recent years, many studies have shown that flaviviruses, especially Dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, Dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. […] NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha beta. […] The presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. […] This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.

• #100 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  In recent years, many studies have shown that flaviviruses, especially Dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, Dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. […] NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha beta. […] The presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. […] This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.

• #101 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  In recent years, many studies have shown that flaviviruses, especially Dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, Dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. […] NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha beta. […] The presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. […] This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.

• #102 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  In recent years, many studies have shown that flaviviruses, especially Dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, Dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. […] NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha beta. […] The presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. […] This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.

• #103 Dengue virus – Wikipedia

  https://en.wikipedia.org/wiki/Dengue_virus

  In recent years, many studies have shown that flaviviruses, especially Dengue virus, has the ability to inhibit the innate immune response during the infection. Indeed, Dengue virus has many nonstructural proteins that allow the inhibition of various mediators of the innate immune system response. […] NS4B is a small, hydrophobic protein located in association with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha beta. […] The presence of this 105-kDa protein results in inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. […] This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-beta promoter; NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.

• #104

  https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue

  Dengue is a viral infection transmitted to humans through the bite of infected mosquitoes. […] Dengue is treated with pain medicine as there is no specific treatment currently. […] The dengue virus is transmitted to humans through the bites of infected female mosquitoes, primarily the Aedes aegypti mosquito. […] After feeding on a infected person, the virus replicates in the mosquito midgut before disseminating to secondary tissues, including the salivary glands. […] The time it takes from ingesting the virus to actual transmission to a new host is termed the extrinsic incubation period (EIP). […] The EIP takes about 8-12 days when the ambient temperature is between 25-28C. […] Variations in the extrinsic incubation period are not only influenced by ambient temperature; several factors such as the magnitude of daily temperature fluctuations, virus genotype, and initial viral concentration can also alter the time it takes for a mosquito to transmit the virus.

• #105

  https://journals.lww.com/co-infectiousdiseases/Fulltext/2013/06000/The_pathogenesis_of_dengue.11.aspx?generateEpub=Article%7Cco-infectiousdiseases:2013:06000:00011%7C%7C

  The pathogenesis of dengue is likely to be a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. Better understanding of the underlying mechanisms leading to severe dengue is crucial if we are to develop prognostic markers, novel diagnostics and therapeutics and ultimately a balanced and safe vaccine.

• #106

  https://www.utmb.edu/research/research-at-utmb/research-facts-figures/article/utmb-news/2020/07/13/utmb-researchers-have-discovered-an-antiviral-mechanism-for-dengue-therapeutics

  Dengue virus is a very important mosquito-transmitted viral pathogen, causing 390 million human infections each year. […] In this study, the UTMB team has solved the co-crystal structure of the dengue capsid protein, which forms the interior of virus, in complex with an inhibitor. The co-crystal structure has provided atomic details of how the inhibitor binds the capsid protein and blocks its normal function, leading to the inhibition of viral infection. […] Our co-crystal structure explains why this is the case, said Pei-Yong Shi, I.H. Kempner professor of Human Genetics at UTMB. Using this new information, we will be able to design new drugs that can inhibit all types of dengue virus. […] Our study also explains how resistance emerges when dengue virus is treated with the inhibitor. A resistant virus emerges through one amino acid change that weakens the compound binding to the viral capsid protein.

• #107

  https://link.springer.com/article/10.1007/s00284-020-02284-w

  The role of immune regulatory mechanisms of the immune system, which are CD4+ FoxP3 expressing regulatory T cells (Tregs), has also been investigated by some researchers. […] A balance between Th1 and Th2 is important for the control of immune response to microorganisms. […] In DENV infection, the Treg cells may suppress protective Th1 response and enhance the Th2 response leading to increase in infection-induced immunopathology. […] The proven role of Treg cells in severe dengue disease has prompted researchers to think about manipulation of this subset of T cells in future for use in patients for treatment by enhancing/depressing their suppressor function.

• #108 Current Understanding of the Pathogenesis of Dengue Virus Infection

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7815537/

  In DENV infection, the Treg cells may suppress protective Th1 response and enhance the Th2 response leading to increase in infection-induced immunopathology. […] The proven role of Treg cells in severe dengue disease has prompted researchers to think about manipulation of this subset of T cells in future for use in patients for treatment by enhancing/depressing their suppressor function.

• #109 Vaccine News — Vax-Before-Travel

  https://www.vax-before-travel.com/vaccine-news

  QDENGA (TAK-003) is a tetravalent, two-dose vaccine approved for preventing dengue fever and/or Severe Dengue caused by any of the four serotypes of the dengue virus. […] Throughout 2025, a second-generation dengue vaccine has been offered in various countries in the Asia-Pacific Region as a disease prevention option. Unfortunately, the QDENGA vaccine is not available in the United States.

• #110 Vaccine News — Vax-Before-Travel

  https://www.vax-before-travel.com/vaccine-news

  QDENGA (TAK-003) is a tetravalent, two-dose vaccine approved for preventing dengue fever and/or Severe Dengue caused by any of the four serotypes of the dengue virus. […] Throughout 2025, a second-generation dengue vaccine has been offered in various countries in the Asia-Pacific Region as a disease prevention option. Unfortunately, the QDENGA vaccine is not available in the United States.

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