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 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

  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. […] During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Furthermore, the virus increases capillary permeability to cause a body fluid loss that results in a hypovolemic shock DSS and multiple organ failures. […] Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis. […] The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak.

• #3 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. […] This limitation is related to the lack of a suitable animal model of 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.

• #4 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. […] Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. […] 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, which is detectable by means of radiology or sonography.

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

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

  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. […] 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.

• #6 Dengue Virus Infection: Etiology, Epidemiology, Pathogenesis, Diagnosis, and Prevention | IntechOpen

  https://www.intechopen.com/chapters/89191

  Dengue fever, a rapidly spreading viral infection, is a global public health concern, particularly in tropical and subtropical climate-prone countries. […] The dengue virus belongs to the Flavivirus genus and Flaviviridae family. It consists of four distinct serotypes of single-stranded positive-sense RNA viruses related to their antigens. The infection can cause various disorders ranging from mild febrile illness to dengue hemorrhagic fever or shock syndrome. […] The genome of DENV is composed of a solitary RNA strand with positive polarity, measuring approximately 10.8 kb in length. It contains an open reading frame that encodes a solitary polyprotein. This polyprotein is subsequently cleaved into the structural proteins capsid (C), membrane (M), and envelope (E), as well as eight nonstructural (NS) proteins, namely NS1, NS2A, NS2B, NS3, NS4A, NS2K, NS4B, and NS5. The structural glycoprotein E facilitates the cell recognition and entry process, which promotes fusion between the viral envelope and the cell membrane. On the other hand, the NS proteins assist in the replication of the viral genome.

• #7 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 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 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 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.

• #9 Dengue virus – Wikipedia

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

  Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus. Four serotypes of the virus have been found, and a reported fifth has yet to be confirmed, all of which can cause the full spectrum of disease. […] The infected mosquito then seeks blood, biting a different human. At this moment, the human’s skin cells get (keratinocytes) infected first. Subsequently, dendritic cells (DC) take up the virus and get infected too. The DC’s mobility disperses virus in the body where some other cell types can get infected, as well (macrophages, hepatocytes and Bone Marrow cells). […] Dengue virus lifecycle in cells, both in arthropod and mammalian cells, is typical for single-stranded (+)-RNA viruses. After binding to specific receptors on the cell the virion gets endocytosed. Endosomes usually get acidified and become lysosomes which digest their content. But the acidic condition triggers a conformational change in the envelope of the virion, making its membrane fuse with the endosome membrane, releasing the viral capsid with the viral RNA genome into the cell’s cytosol.

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

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

  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. […] 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.

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

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

  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

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

  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. […] 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). […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

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

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

  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.

• #14 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 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. […] A recent report suggested that NS1 activates macrophages via Toll-like receptor 4 (TLR4) and disrupts endothelial cells, resulting in vascular leakage as mentioned in Fig. 2A. […] The importance of the NS3 protein for the survival of the virus makes it a target for antiviral drugs as mentioned in Table 2. […] The DENV envelope protein is involved in attachment and host cell receptor binding for virus entry into the host cell as mentioned in Fig. 2D. […] 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.

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

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

  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.

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

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

  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.

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

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

  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. […] Dengue NS1 causes complement activation which is a host defense mechanism against the infection. […] The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9.

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

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

  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. […] Dengue NS1 causes complement activation which is a host defense mechanism against the infection. […] The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9.

• #19

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

  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. […] 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). […] DENV NS1 can directly trigger complement activation by the alternative pathway, targeting liver cells which leads to the stimulation of inflammatory cytokines.

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

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

  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. […] Dengue NS1 causes complement activation which is a host defense mechanism against the infection. […] The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9.

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

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

  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. […] Dengue NS1 causes complement activation which is a host defense mechanism against the infection. […] The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9.

• #22

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

  The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9. […] DENV NS1-mediated activation of cathepsin L/heparanase pathway and endothelial sialidases may lead to disruption of the endothelial glycocalyx-like layer (EGL) in vitro. […] 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. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis.

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

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

  The C5b-C9 complex can stimulate robust expression of inflammatory cytokines that are associated with DHF development. […] C5b-C9 complex formation which is often associated with DHF has been found to have a significant association with DENV NS1 levels. […] The activation of complement also generates anaphylatoxins C5a and C3a, which also play a significant role in the inflammatory process. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis. […] In some recent studies, anti-NS1 antibodies were seen to result in autoimmunity, thus contributing to the development of severe dengue. […] There are numerous self-antigens, which are known to exhibit sequence homology with DENV NS1 protein.

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

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

  The C5b-C9 complex can stimulate robust expression of inflammatory cytokines that are associated with DHF development. […] C5b-C9 complex formation which is often associated with DHF has been found to have a significant association with DENV NS1 levels. […] The activation of complement also generates anaphylatoxins C5a and C3a, which also play a significant role in the inflammatory process. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis. […] In some recent studies, anti-NS1 antibodies were seen to result in autoimmunity, thus contributing to the development of severe dengue. […] There are numerous self-antigens, which are known to exhibit sequence homology with DENV NS1 protein.

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

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

  The C5b-C9 complex can stimulate robust expression of inflammatory cytokines that are associated with DHF development. […] C5b-C9 complex formation which is often associated with DHF has been found to have a significant association with DENV NS1 levels. […] The activation of complement also generates anaphylatoxins C5a and C3a, which also play a significant role in the inflammatory process. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis. […] In some recent studies, anti-NS1 antibodies were seen to result in autoimmunity, thus contributing to the development of severe dengue. […] There are numerous self-antigens, which are known to exhibit sequence homology with DENV NS1 protein.

• #26

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

  The end result of complement activation is the lysis of target cells through the assembly of the membrane attack complex (MAC), which is composed of complement proteins C5b-C9. […] DENV NS1-mediated activation of cathepsin L/heparanase pathway and endothelial sialidases may lead to disruption of the endothelial glycocalyx-like layer (EGL) in vitro. […] 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. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis.

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

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

  The C5b-C9 complex can stimulate robust expression of inflammatory cytokines that are associated with DHF development. […] C5b-C9 complex formation which is often associated with DHF has been found to have a significant association with DENV NS1 levels. […] The activation of complement also generates anaphylatoxins C5a and C3a, which also play a significant role in the inflammatory process. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis. […] In some recent studies, anti-NS1 antibodies were seen to result in autoimmunity, thus contributing to the development of severe dengue. […] There are numerous self-antigens, which are known to exhibit sequence homology with DENV NS1 protein.

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

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

  The C5b-C9 complex can stimulate robust expression of inflammatory cytokines that are associated with DHF development. […] C5b-C9 complex formation which is often associated with DHF has been found to have a significant association with DENV NS1 levels. […] The activation of complement also generates anaphylatoxins C5a and C3a, which also play a significant role in the inflammatory process. […] Molecular mimicry and autoimmunity have been demonstrated in Coxsackievirus and Epstein-Barr virus infections. […] Similarly, autoantibodies have also been associated as a significant factor involved in dengue virus pathogenesis. […] In some recent studies, anti-NS1 antibodies were seen to result in autoimmunity, thus contributing to the development of severe dengue. […] There are numerous self-antigens, which are known to exhibit sequence homology with DENV NS1 protein.

• #29 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 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.

• #30

  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. […] 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. […] The severe dengue manifestations in humans are mainly ascribed to the synergistic effect of all the above-mentioned factors.

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

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

  Apart from DENV NS1, molecular mimicry has also been reported with other proteins such as DENV prM and E proteins, elucidating the cross-reactivity of the antibody against these antigens too. […] The role of anti-NS1 antibodies in autoimmunity during dengue virus infection has been proposed in vitro and in animal studies but its contribution in dengue patients is still not clearly proven due to lack of sufficient data.

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

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

  Apart from DENV NS1, molecular mimicry has also been reported with other proteins such as DENV prM and E proteins, elucidating the cross-reactivity of the antibody against these antigens too. […] The role of anti-NS1 antibodies in autoimmunity during dengue virus infection has been proposed in vitro and in animal studies but its contribution in dengue patients is still not clearly proven due to lack of sufficient data.

• #33

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

  The role of anti-NS1 antibodies in autoimmunity during dengue virus infection has been proposed in vitro and in animal studies but its contribution in dengue patients is still not clearly proven due to lack of sufficient data. […] Severe dengue disease has been associated with all the four DENV serotypes. […] However, due to genetic differences between various DENV genotypes, each genotype has a difference in virulence as well as epidemic potential. […] 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.

• #34 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.

• #35 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. […] Increased frequencies of DENV-specific T cells were observed in acute DENV infection, and these cells represented activated phenotypes. […] The presence of soluble markers of T cell activation, including sIL-2R, sTNFR, and sCD8, indicate systemic T cell activation. […] Development of DENV-specific cross-reactive CD8 T cells occurs following both primary and secondary infection. However, these cells do not correlate with the disease severity.

• #36 Dengue: Practice Essentials, Background, Pathophysiology

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

  The immunopathology of severe dengue remains incompletely understood. […] When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody complex. […] 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. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis.

• #37 Dengue: Practice Essentials, Background, Pathophysiology

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

  The immunopathology of severe dengue remains incompletely understood. […] When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody complex. […] 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. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis.

• #38 Dengue: Practice Essentials, Background, Pathophysiology

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

  The immunopathology of severe dengue remains incompletely understood. […] When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody complex. […] 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. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis.

• #39 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 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.

• #40 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. […] Increased frequencies of DENV-specific T cells were observed in acute DENV infection, and these cells represented activated phenotypes. […] The presence of soluble markers of T cell activation, including sIL-2R, sTNFR, and sCD8, indicate systemic T cell activation. […] Development of DENV-specific cross-reactive CD8 T cells occurs following both primary and secondary infection. However, these cells do not correlate with the disease severity.

• #41 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. […] Increased frequencies of DENV-specific T cells were observed in acute DENV infection, and these cells represented activated phenotypes. […] The presence of soluble markers of T cell activation, including sIL-2R, sTNFR, and sCD8, indicate systemic T cell activation. […] Development of DENV-specific cross-reactive CD8 T cells occurs following both primary and secondary infection. However, these cells do not correlate with the disease severity.

• #42 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. […] Increased frequencies of DENV-specific T cells were observed in acute DENV infection, and these cells represented activated phenotypes. […] The presence of soluble markers of T cell activation, including sIL-2R, sTNFR, and sCD8, indicate systemic T cell activation. […] Development of DENV-specific cross-reactive CD8 T cells occurs following both primary and secondary infection. However, these cells do not correlate with the disease severity.

• #43 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.

• #44 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). […] Macrophage migration inhibitory factor (MIF) is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. […] The antibody-dependent enhancement (ADE) theory of dengue pathogenesis was first proposed by Halstead in 1977 to explain the phenomenon in which secondary infection with different serotypes of DENV may cause more severe disease development. […] The association of cytokines in dengue patients with severe dengue has been widely studied. […] During the early febrile phase, the first wave of antiviral cytokines, such as type I interferon (IFN), and proinflammatory cytokines, such as macrophage migration inhibitory factor (MIF), monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-6, and IL-8, are produced by initially exposed cells, such as epidermal dendritic cells and endothelial cells, and these factors can be released immediately.

• #45 Dengue: Practice Essentials, Background, Pathophysiology

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

  Once inoculated into a human host, dengue has an incubation period of 3-14 days, (average 4-7 days) whereas viral replication takes place in target dendritic cells. […] 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. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.

• #46 Dengue: Practice Essentials, Background, Pathophysiology

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

  Once inoculated into a human host, dengue has an incubation period of 3-14 days, (average 4-7 days) whereas viral replication takes place in target dendritic cells. […] 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. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.

• #47 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  At the time of plasma leakage, elevated levels of permeability-enhancing factors, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A (VEGFA) are found in severe dengue patients and contribute to three main pathological features: plasma leakage, hemorrhage and coagulopathy. […] Among these cytokines, MIF is the only cytokine that is preformed inside cells and can be secreted very early during infection. […] MIF can promote the synthesis of proinflammatory cytokines, such as TNF, IFN-γ, IL-1β, IL-2, IL-6, and IL-8, to further amplify the production of other proinflammatory cytokines. […] The first evidence of the pathogenic role of MIF in dengue disease was indicated by the positive correlation between the MIF level in the sera of dengue patients and disease severity.

• #48 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 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.

• #49 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

  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. […] During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Furthermore, the virus increases capillary permeability to cause a body fluid loss that results in a hypovolemic shock DSS and multiple organ failures. […] Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis. […] The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak.

• #50 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. […] Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. […] 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, which is detectable by means of radiology or sonography.

• #51 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. […] Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. […] 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, which is detectable by means of radiology or sonography.

• #52 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  Dengue virus (DENV) infection is the most prevalent mosquito-borne viral infection and can lead to severe dengue hemorrhagic fever (DHF) and even life-threatening dengue shock syndrome (DSS). […] Macrophage migration inhibitory factor (MIF) is involved in DENV replication and many pathological changes, such as vascular leakage, during DENV infection. […] The antibody-dependent enhancement (ADE) theory of dengue pathogenesis was first proposed by Halstead in 1977 to explain the phenomenon in which secondary infection with different serotypes of DENV may cause more severe disease development. […] The association of cytokines in dengue patients with severe dengue has been widely studied. […] During the early febrile phase, the first wave of antiviral cytokines, such as type I interferon (IFN), and proinflammatory cytokines, such as macrophage migration inhibitory factor (MIF), monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-6, and IL-8, are produced by initially exposed cells, such as epidermal dendritic cells and endothelial cells, and these factors can be released immediately.

• #53 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  At the time of plasma leakage, elevated levels of permeability-enhancing factors, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A (VEGFA) are found in severe dengue patients and contribute to three main pathological features: plasma leakage, hemorrhage and coagulopathy. […] Among these cytokines, MIF is the only cytokine that is preformed inside cells and can be secreted very early during infection. […] MIF can promote the synthesis of proinflammatory cytokines, such as TNF, IFN-γ, IL-1β, IL-2, IL-6, and IL-8, to further amplify the production of other proinflammatory cytokines. […] The first evidence of the pathogenic role of MIF in dengue disease was indicated by the positive correlation between the MIF level in the sera of dengue patients and disease severity.

• #54 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  At the time of plasma leakage, elevated levels of permeability-enhancing factors, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A (VEGFA) are found in severe dengue patients and contribute to three main pathological features: plasma leakage, hemorrhage and coagulopathy. […] Among these cytokines, MIF is the only cytokine that is preformed inside cells and can be secreted very early during infection. […] MIF can promote the synthesis of proinflammatory cytokines, such as TNF, IFN-γ, IL-1β, IL-2, IL-6, and IL-8, to further amplify the production of other proinflammatory cytokines. […] The first evidence of the pathogenic role of MIF in dengue disease was indicated by the positive correlation between the MIF level in the sera of dengue patients and disease severity.

• #55 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  At the time of plasma leakage, elevated levels of permeability-enhancing factors, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor-A (VEGFA) are found in severe dengue patients and contribute to three main pathological features: plasma leakage, hemorrhage and coagulopathy. […] Among these cytokines, MIF is the only cytokine that is preformed inside cells and can be secreted very early during infection. […] MIF can promote the synthesis of proinflammatory cytokines, such as TNF, IFN-γ, IL-1β, IL-2, IL-6, and IL-8, to further amplify the production of other proinflammatory cytokines. […] The first evidence of the pathogenic role of MIF in dengue disease was indicated by the positive correlation between the MIF level in the sera of dengue patients and disease severity.

• #56 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  DENV infection can stimulate MIF secretion from HuH-7 cells. […] DENV NS1 can activate MIF secretion in endothelial cells, which triggers the release of heparan sulfate-specific heparanase 1 (HPA-1) and endothelial glycocalyx shedding. […] MIF plays important roles in vascular leakage during DENV infection. […] MIF can lead to coagulopathy and vascular leakage through DENV-stimulated immune cells, which may explain why the increased hematocrit was attenuated in DENV2-infected Mif−/− mice. […] MIF is required for NET formation in immune disorders. […] MIF is known to be released from the intracellular pools very quickly upon stimulation. […] DENV infection triggers MIF expression and secretion, which enhances DENV2 replication in HuH-7 cells. […] MIF is crucial in the vasculature, which has been addressed in several studies. […] MIF contributes to the pathogenesis of various viral infections, including human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), West Nile virus (WNV) and DENV.

• #57 Roles of Macrophage Migration Inhibitory Factor in Dengue Pathogenesis: From Pathogenic Factor to Therapeutic Target

  https://www.mdpi.com/2076-2607/8/6/891

  DENV infection can stimulate MIF secretion from HuH-7 cells. […] DENV NS1 can activate MIF secretion in endothelial cells, which triggers the release of heparan sulfate-specific heparanase 1 (HPA-1) and endothelial glycocalyx shedding. […] MIF plays important roles in vascular leakage during DENV infection. […] MIF can lead to coagulopathy and vascular leakage through DENV-stimulated immune cells, which may explain why the increased hematocrit was attenuated in DENV2-infected Mif−/− mice. […] MIF is required for NET formation in immune disorders. […] MIF is known to be released from the intracellular pools very quickly upon stimulation. […] DENV infection triggers MIF expression and secretion, which enhances DENV2 replication in HuH-7 cells. […] MIF is crucial in the vasculature, which has been addressed in several studies. […] MIF contributes to the pathogenesis of various viral infections, including human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), West Nile virus (WNV) and DENV.

• #58

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

  DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. […] The neurological manifestations in dengue infection are caused mainly by DENV-2 and DENV-3. […] Severe dengue includes central nervous system (CNS) impairment. […] The neuropathogenesis of DENV infection needs to be clarified. 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.

• #59

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

  DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. […] The neurological manifestations in dengue infection are caused mainly by DENV-2 and DENV-3. […] Severe dengue includes central nervous system (CNS) impairment. […] The neuropathogenesis of DENV infection needs to be clarified. 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.

• #60

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

  DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. […] The neurological manifestations in dengue infection are caused mainly by DENV-2 and DENV-3. […] Severe dengue includes central nervous system (CNS) impairment. […] The neuropathogenesis of DENV infection needs to be clarified. 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.

• #61

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

  DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. […] The neurological manifestations in dengue infection are caused mainly by DENV-2 and DENV-3. […] Severe dengue includes central nervous system (CNS) impairment. […] The neuropathogenesis of DENV infection needs to be clarified. 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.

• #62

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

  DENV can access the nervous system through blood-brain barrier disturbance mediated by cytokine. […] The blood-cerebrospinal fluid (CSF) barrier seems to be also involved, considering the presence of the virus in the CSF of patients with neurological manifestations. […] The neurological manifestations in dengue infection are caused mainly by DENV-2 and DENV-3. […] Severe dengue includes central nervous system (CNS) impairment. […] The neuropathogenesis of DENV infection needs to be clarified. 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.

• #63

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

  A study developed in mice showed that DENV can breakdown the blood-brain barrier (BBB). […] During the infection, there is an over-expression of cytokines, that alter the permeability of the endothelium through the disturbance of the tight junctions. […] In fact, the break of BBB in dengue infection was associated with high levels of plasmatic metalloproteinase 9 (MMP-9). […] Moreover, DENV-2-infected monocytes express monocyte chemoattractant protein-1 (MCP-1). […] Therefore, DENV is able to enter in the CNS. […] Another hypothesis is that dengue virus can access the nervous system, crossing the endothelial cells through transcytosis. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] DENV RNA was also detected in brain tissue and in CSF of infected individuals.

• #64

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

  A study developed in mice showed that DENV can breakdown the blood-brain barrier (BBB). […] During the infection, there is an over-expression of cytokines, that alter the permeability of the endothelium through the disturbance of the tight junctions. […] In fact, the break of BBB in dengue infection was associated with high levels of plasmatic metalloproteinase 9 (MMP-9). […] Moreover, DENV-2-infected monocytes express monocyte chemoattractant protein-1 (MCP-1). […] Therefore, DENV is able to enter in the CNS. […] Another hypothesis is that dengue virus can access the nervous system, crossing the endothelial cells through transcytosis. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] DENV RNA was also detected in brain tissue and in CSF of infected individuals.

• #65

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

  A study developed in mice showed that DENV can breakdown the blood-brain barrier (BBB). […] During the infection, there is an over-expression of cytokines, that alter the permeability of the endothelium through the disturbance of the tight junctions. […] In fact, the break of BBB in dengue infection was associated with high levels of plasmatic metalloproteinase 9 (MMP-9). […] Moreover, DENV-2-infected monocytes express monocyte chemoattractant protein-1 (MCP-1). […] Therefore, DENV is able to enter in the CNS. […] Another hypothesis is that dengue virus can access the nervous system, crossing the endothelial cells through transcytosis. […] There are several evidences that dengue virus is able to infect and replicate in neural cells. This ability is called neurotropism. […] DENV RNA was also detected in brain tissue and in CSF of infected individuals.

• #66 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. […] 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.

• #67 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. […] 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.

• #68 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. […] 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.

• #69 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

  DENV causes platelet reduction in patients, beginning typically on day 2 before the onset of the critical phase and persisting until days 6-7. 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. […] In short, DENV can infect megakaryocytes at different stages of cell maturation and impair platelet production, leading to reduced platelet formation.

• #70 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

  DENV causes platelet reduction in patients, beginning typically on day 2 before the onset of the critical phase and persisting until days 6-7. 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. […] In short, DENV can infect megakaryocytes at different stages of cell maturation and impair platelet production, leading to reduced platelet formation.

• #71 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 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 2.5-3.5 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.

• #72

  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. […] 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. […] 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.

• #73

  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. […] 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. […] 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.

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

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

  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. […] 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.

• #75 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

  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 severities of DF are likely to be multi-factorial, though the mechanisms leading to severe are yet to be understood.

• #76 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

  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 severities of DF are likely to be multi-factorial, though the mechanisms leading to severe are yet to be understood.

• #77

  https://www.jci.org/articles/view/131170

  Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. […] In severe dengue disease, plasma leakage occurs later in infection, after the waning of fever and viremia. As such, plasma leakage is likely due to host-immune or mediator-induced response as opposed to endothelial cell infection and consequent destruction. […] Mechanistically, the study authors hypothesize that tryptase induces increased vascular permeability and leakage by reducing the expression of the cellular adhesion molecule CD31 on endothelial cells, resulting in the loss of tight junctions.

• #78 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 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.

• #79 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

  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. […] During severe DF cases, the DENV induces blood coagulation abnormality and plasma leakage and increases vascular fragility to lead to DHF. Furthermore, the virus increases capillary permeability to cause a body fluid loss that results in a hypovolemic shock DSS and multiple organ failures. […] Hence, the patho-physiological features of severe DF may be due to plasma leakage and abnormal hemostasis. […] The DENV infection severity peaks after the virus has been cleared by the host immune system, not during the viral load is at peak.

• #80 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.

• #81 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

  It is an important finding to confirm that the host immune response plays a crucial role in the pathogenesis of DENV infection. […] 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.

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