Materiały źródłowe

• #1 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  Histoplasmosis is a systemic mycosis caused by the thermally dimorphic fungus Histoplasma capsulatum. […] In this review, we discuss the established virulence factors and pathogenesis traits that make H. capsulatum highly adapted to a wide variety of hosts, including mammals. Understanding and integrating these mechanisms is a key step toward devising new preventative and therapeutic interventions. […] The onset of infection occurs through the inhalation of microconidia or mycelial fragments by the host. This step is followed by the deposition of fungal propagules into the pulmonary alveoli and a rapid conversion to the yeast morphology, triggered by the fungal response to the temperature switch. H. capsulatum yeasts have an optimal growth at 37 C. Morphological changes can occur even before microconidia reach the lungs or within the intracellular environment.

• #2 Frontiers | Immunoproteomics Reveals Pathogen’s Antigens Involved in Homo sapiens–Histoplasma capsulatum Interaction and Specific Linear B-Cell Epitopes in Histoplasmosis

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591121/full

  Histoplasmosis is one of the most frequent systemic mycosis in HIV patients. In these patients, histoplasmosis has high rates of morbidity/mortality if diagnosis and treatment are delayed. […] The infection by H. capsulatum depends on a complex interaction between the fungus and the mammalian host, with disease prognosis determined by factors such as immune status of the host, strain virulence, and inhaled fungal burden. Although histoplasmosis affects either immunologically intact or deficient hosts, individuals with compromised cellular immune response presents more severe manifestations of this disease. The yeast cells of H. capsulatum are highly adapted to the host since they can survive and reproduce within phagocytic cells. Histoplasma capsulatum strategies against macrophages include evasion from the immune response on entry, inactivation of nitrogen and oxygen reactive species, prevention of phagolysosomal fusion, hindrance of lysosomal pH reduction, siderophore production, and induction of apoptosis for escape and dissemination into the host.

• #3

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  H. capsulatum yeast cells are highly adapted to the mammalian host as they can effectively survive within intracellular niches in select phagocytic cells. […] Once Histoplasma enters the host, it must evade immune-mediated and intracellular defenses, and find a favorable niche for growth and reproduction, which may include dissemination and the development of a state of latency within granulomas. […] The pathogens ability to evade inflammatory responses and the intensity of the host immune response determine the severity of symptoms and clinical presentation, and whether a state of latency develops with the potential for reactivation. […] The yeast is the pathogenic form of H. capsulatum causing acute disease, or it can become latent, able to potentially reemerge in the setting of immunosuppression. However, H. capsulatum has many obstacles to overcome to cause host injury. It must bypass mucosal barriers during acute inoculation, evade host immune cell responses, and find its niche within host macrophages.

• #4

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  When H. capsulatum successfully enters macrophages, it can effectively avoid host effector responses and multiply. Within these cells, the fungus can disseminate throughout the host organs. […] H. capsulatum pathogenesis begins immediately upon contact with the host. Upon entry into to the host and the shift to mammalian body temperature, the mycelial form ceases to be metabolically active. […] The transition can be inhibited by sulfhydryl blocking agents, which lock the fungus in the mycelial phase. Significantly, using this blocking system, treated H. capsulatum is unable to cause disease in well-established animal models, which highlights the necessity of the transformation into the yeast form for virulence. […] Once they reach alveoli, H. capsulatum yeast encounter cells of innate immune system. While shown to interact with various cell types, as part of the innate immune response, yeast cells establish their niche within alveolar macrophages.

• #5

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  When H. capsulatum successfully enters macrophages, it can effectively avoid host effector responses and multiply. Within these cells, the fungus can disseminate throughout the host organs. […] H. capsulatum pathogenesis begins immediately upon contact with the host. Upon entry into to the host and the shift to mammalian body temperature, the mycelial form ceases to be metabolically active. […] The transition can be inhibited by sulfhydryl blocking agents, which lock the fungus in the mycelial phase. Significantly, using this blocking system, treated H. capsulatum is unable to cause disease in well-established animal models, which highlights the necessity of the transformation into the yeast form for virulence. […] Once they reach alveoli, H. capsulatum yeast encounter cells of innate immune system. While shown to interact with various cell types, as part of the innate immune response, yeast cells establish their niche within alveolar macrophages.

• #6 Histoplasma capsulatum Pathogenesis | J. Craig Venter Institute

  https://www.jcvi.org/research/histoplasma-capsulatum-pathogenesis

  Our prior research findings significantly contributed to the understanding of the molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: she found that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting regulatory network. […] Specifically, downstream targets of the Ryp proteins will be tested for their role in pathogenesis. […] Additionally, we are investigating factors that regulate Ryp proteins in response to host temperature. […] These studies will provide fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host.

• #7 Pathogenesis and clinical manifestations of disseminated histoplasmosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis

  Pathogenesis of disseminated histoplasmosis, risk factors for dissemination, and clinical features of the infection will be reviewed here. […] Histoplasma capsulatum is a thermally dimorphic fungus, growing as a mold in the environment and as a yeast at 37°C. Infection develops when Histoplasma microconidia are inhaled into the lungs, where they change into the yeast form. Neutrophils, macrophages, lymphocytes, and natural killer (NK) cells are attracted in response to the infection. As in tuberculosis, macrophages assist in spreading the organism via lymphatics to the adjacent lymph nodes and from there by hematogenous spread throughout the reticuloendothelial system (liver, spleen, lymph nodes, and bone marrow). […] In patients with disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. Organisms are confined to macrophages but less commonly can be seen within the tissue spaces as well as in peripheral white blood cells.

• #8 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  Pathogenesis results from the initial adaptation to the host environment followed by a successful interaction with the innate immune system. H. capsulatum can survive the intracellular environment of phagocytes and evade the effector responses of the host immune system, multiplying, and being carried to the lymph nodes, where they gain access to blood circulation, and can spread to different tissues and organs, characterizing histoplasmosis in its invasive form. […] H. capsulatum combines virulence factors and regulators that are effectively used to defeat the hosts innate and adaptive immune response. […] Morphological transitions are a major aspect of H. capsulatum’s capacity to cause disease as the inhaled conidia and mycelial fragments do not express several of the virulence factors observed in the yeast morphology. Temperature is by far the most exploited trigger to morphological changes.

• #9

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  To persist within this vacuole, it must evade further protective responses to an invading organism. The ways that it alters normal function include inactivating phagasomal reactive nitrogen and oxygen species, prevention of phagosomal acidification, and potentially lysosomal fusion. […] The pathogen, if successful, can continue to grow and divide in this host cell, and eventually will travel to the nucleus to induce host cell apoptosis so that it can infect other cells and disseminate. […] H. capsulatum has defense mechanisms in place to evade both reactive oxygen and nitrogen species. But these are not the only dangers to the pathogen when it exists intracellularly and within a phagocytic vacuole. […] The processes discussed thus far have focused on the initial entry and phagocytosis by macrophages. Once inside, Histoplasma survives within a phagocytic vacuole in the cytoplasm. To persist and grow in this compartment, it needs to overcome additional challenges. Most of the fungus actions are defensive in nature. It must inactivate reactive oxygen and nitrogen species released into the vacuole, prevent phagosome acidification and lysosomal fusion, and produce and transport needed nutrients to overcome nutritional immunity of the macrophage.

• #10 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  H. capsulatum is well known for enduring high concentrations of reactive oxygen species (ROS). […] H. capsulatum yeasts are able to regulate phagosome acidification and prevent lysosomal fusion as part of their strategy to survive in the intracellular space. […] Taken together, the studies reviewed above emphasize that the different strategies that H. capsulatum employs to acquire nutrients are absolutely necessary for the fungus to thrive in the intracellular environment of macrophages, being an integral part of pathogenesis, as without those, the establishment of the niche within these cells would fail, preventing the development of histoplasmosis.

• #11 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  H. capsulatum is well known for enduring high concentrations of reactive oxygen species (ROS). […] H. capsulatum yeasts are able to regulate phagosome acidification and prevent lysosomal fusion as part of their strategy to survive in the intracellular space. […] Taken together, the studies reviewed above emphasize that the different strategies that H. capsulatum employs to acquire nutrients are absolutely necessary for the fungus to thrive in the intracellular environment of macrophages, being an integral part of pathogenesis, as without those, the establishment of the niche within these cells would fail, preventing the development of histoplasmosis.

• #12

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  To persist within this vacuole, it must evade further protective responses to an invading organism. The ways that it alters normal function include inactivating phagasomal reactive nitrogen and oxygen species, prevention of phagosomal acidification, and potentially lysosomal fusion. […] The pathogen, if successful, can continue to grow and divide in this host cell, and eventually will travel to the nucleus to induce host cell apoptosis so that it can infect other cells and disseminate. […] H. capsulatum has defense mechanisms in place to evade both reactive oxygen and nitrogen species. But these are not the only dangers to the pathogen when it exists intracellularly and within a phagocytic vacuole. […] The processes discussed thus far have focused on the initial entry and phagocytosis by macrophages. Once inside, Histoplasma survives within a phagocytic vacuole in the cytoplasm. To persist and grow in this compartment, it needs to overcome additional challenges. Most of the fungus actions are defensive in nature. It must inactivate reactive oxygen and nitrogen species released into the vacuole, prevent phagosome acidification and lysosomal fusion, and produce and transport needed nutrients to overcome nutritional immunity of the macrophage.

• #13 Pulmonary Histoplasmosis: A Clinical Update

  https://www.mdpi.com/2309-608X/9/2/236

  Once in the alveoli, H. capsulatum evades the soluble pattern-recognition receptors, collectins (surfactant protein A and surfactant protein D), and rapid internalization into macrophages. Yeasts can be internalized by other phagocytes, including dendritic cells, neutrophils, and natural killer cells, but are incapable of surviving within them. […] The heat shock protein 60 (Hsp60) of H. capsulatum is the major surface adhesin to macrophages and binds to complement receptor 3 (CR3). Dectin-1 recognizes 1-3 β glucan which is a major polysaccharide in the cell wall of most fungal pathogens. Engagement of Dectin-1 leads to production of pro-inflammatory cytokines, including TNF-α and IL-6. H. capsulatum expresses an outer layer of 1-3 α glucan concealing the 1–3 β D glucans impairing the recognition by Dectin-1. In addition, the H antigen is a beta-glucosidase that remodels the yeast cell wall and is involved in nutrient acquisition. Altogether, the Hsp60-CR3 engagement, while avoiding dectin-1, leads to yeast internalization without triggering pro-inflammatory cascades.

• #14 Pulmonary Histoplasmosis: A Clinical Update

  https://www.mdpi.com/2309-608X/9/2/236

  Once in the alveoli, H. capsulatum evades the soluble pattern-recognition receptors, collectins (surfactant protein A and surfactant protein D), and rapid internalization into macrophages. Yeasts can be internalized by other phagocytes, including dendritic cells, neutrophils, and natural killer cells, but are incapable of surviving within them. […] The heat shock protein 60 (Hsp60) of H. capsulatum is the major surface adhesin to macrophages and binds to complement receptor 3 (CR3). Dectin-1 recognizes 1-3 β glucan which is a major polysaccharide in the cell wall of most fungal pathogens. Engagement of Dectin-1 leads to production of pro-inflammatory cytokines, including TNF-α and IL-6. H. capsulatum expresses an outer layer of 1-3 α glucan concealing the 1–3 β D glucans impairing the recognition by Dectin-1. In addition, the H antigen is a beta-glucosidase that remodels the yeast cell wall and is involved in nutrient acquisition. Altogether, the Hsp60-CR3 engagement, while avoiding dectin-1, leads to yeast internalization without triggering pro-inflammatory cascades.

• #15 Pathogenesis and clinical manifestations of disseminated histoplasmosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis

  Pathogenesis of disseminated histoplasmosis, risk factors for dissemination, and clinical features of the infection will be reviewed here. […] Histoplasma capsulatum is a thermally dimorphic fungus, growing as a mold in the environment and as a yeast at 37°C. Infection develops when Histoplasma microconidia are inhaled into the lungs, where they change into the yeast form. Neutrophils, macrophages, lymphocytes, and natural killer (NK) cells are attracted in response to the infection. As in tuberculosis, macrophages assist in spreading the organism via lymphatics to the adjacent lymph nodes and from there by hematogenous spread throughout the reticuloendothelial system (liver, spleen, lymph nodes, and bone marrow). […] In patients with disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. Organisms are confined to macrophages but less commonly can be seen within the tissue spaces as well as in peripheral white blood cells.

• #16 Overview of Histoplasmosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/1215/p2247.html

  When spores produced by the mycelial form of H. capsulatum become airborne, they are inhaled and deposited in alveoli. At normal body temperature (37C [98.6F]), the spores germinate into the yeast form of this dimorphic fungus and are ingested by pulmonary macrophages. The yeasts become parasitic, multiply within these cells, and travel to hilar and mediastinal lymph nodes, where they gain access to the blood circulation that disseminates them to various organs. Macrophages throughout the reticuloendothelial system ingest and sequester the organism. […] About 10 to 14 days after exposure, cellular immunity develops, and macrophages become fungicidal and clear an immunocompetent host of infection. Necrosis develops at the sites of infection in the lungs, lymph nodes, liver, spleen, and bone marrow, leading to caseation, fibrous encapsulation, calcium deposition and, within a few years of the primary infection, calcified granulomas. Any defects in cellular immunity result in a progressive disseminated form of infection that can be lethal.

• #17

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  The entire mechanism of fungistasis by these proteins has not been fully elucidated. […] The pathogen needs to be able to utilize what is present or produce its own nutrients to meet its metabolic needs. […] H. capsulatum, by utilizing the previously discussed interactions with the host macrophage, can thrive in its intracellular niche. However, for infection to be propagated in the host and disseminate to other organs in the body, the pathogen needs to induce apoptosis of or otherwise leave the macrophage and infect subsequent phagocytes. […] The adaptive immune response once effectively activated can either clear the organism or lead to granuloma formation. If the latter occurs, there is the potential for reactivation of the organism. Reactivation is a response to impaired immunity.

• #18 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  Understanding the genetic and molecular regulators and mechanisms involved in the mycelia-to-yeast transition, which seems to be the key for the successful infectious process, could lead to new prophylactic measures or to the development of therapeutic alternatives to tackle histoplasmosis at the onset of infection. […] H. capsulatum yeasts use macrophages to disseminate to other tissues. Further, yeast cells may induce apoptosis or somehow leave the infected macrophage and move to a subsequent phagocyte. […] The correlation between molecules produced by Histoplasma and host cell death has been investigated by Isaac et al., the authors found three mutants, lacking CBP1 expression, while searching for mutants that would thrive in the intracellular space, but without lysing the host cells.

• #19 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  Understanding the genetic and molecular regulators and mechanisms involved in the mycelia-to-yeast transition, which seems to be the key for the successful infectious process, could lead to new prophylactic measures or to the development of therapeutic alternatives to tackle histoplasmosis at the onset of infection. […] H. capsulatum yeasts use macrophages to disseminate to other tissues. Further, yeast cells may induce apoptosis or somehow leave the infected macrophage and move to a subsequent phagocyte. […] The correlation between molecules produced by Histoplasma and host cell death has been investigated by Isaac et al., the authors found three mutants, lacking CBP1 expression, while searching for mutants that would thrive in the intracellular space, but without lysing the host cells.

• #20 Overview of Histoplasmosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/1215/p2247.html

  When spores produced by the mycelial form of H. capsulatum become airborne, they are inhaled and deposited in alveoli. At normal body temperature (37C [98.6F]), the spores germinate into the yeast form of this dimorphic fungus and are ingested by pulmonary macrophages. The yeasts become parasitic, multiply within these cells, and travel to hilar and mediastinal lymph nodes, where they gain access to the blood circulation that disseminates them to various organs. Macrophages throughout the reticuloendothelial system ingest and sequester the organism. […] About 10 to 14 days after exposure, cellular immunity develops, and macrophages become fungicidal and clear an immunocompetent host of infection. Necrosis develops at the sites of infection in the lungs, lymph nodes, liver, spleen, and bone marrow, leading to caseation, fibrous encapsulation, calcium deposition and, within a few years of the primary infection, calcified granulomas. Any defects in cellular immunity result in a progressive disseminated form of infection that can be lethal.

• #21 Histoplasmosis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/299054-overview

  Histoplasma capsulatum in the saprobic state grows in the mycelial form. […] The aerosolization of conidia and mycelial fragments from contaminated soil results in alveolar deposition via inhalation. […] Conversion from the mycelial to the pathogenic yeast form occurs intracellularly. After phagocytosis by macrophages, the yeast replicates in approximately 15-18 hours. Despite fusion with lysosomes, multiplication continues within the phagosomes. Proposed theories suggest that the yeasts may produce proteins that inhibit the activity of lysosomal proteases. […] As the host immunity response develops, yeast growth ceases within 1-2 weeks after exposure. Cytokines systemically activate the fungistatic activity of macrophages against intracellular yeasts. […] With further maturation of the cell-mediated response, delayed-type hypersensitivity to histoplasmal antigens occurs (3-6 wk after exposure).

• #22 Pathogenesis and clinical manifestations of disseminated histoplasmosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis

  T cell immunity plays the predominant role in recovery from histoplasmosis. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Cytokines including interleukin (IL)-12 and interferon (IFN)-gamma trigger macrophages to kill the fungus and halt progression of disease.

• #23 Pathogenesis and clinical manifestations of disseminated histoplasmosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis/print

  In patients with disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. Organisms are confined to macrophages but less commonly can be seen within the tissue spaces as well as in peripheral white blood cells. […] T cell immunity plays the predominant role in recovery from histoplasmosis. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Cytokines including interleukin (IL)-12 and interferon (IFN)-gamma trigger macrophages to kill the fungus and halt progression of disease.

• #24 Pulmonary Histoplasmosis: A Clinical Update

  https://www.mdpi.com/2309-608X/9/2/236

  Once inside the macrophage, Histoplasma evades reactive oxygen and nitrogen species and is also able to regulate the phagosome acidification and the phagolysosomal fusion. The M antigen, also known as catalase B, counteracts the oxidative stress from the host’s defense mechanisms. Within the macrophages, the yeast reproduces by budding into daughter yeast (narrow budding). […] Macrophages are able to migrate to other areas of the body, and H. capsulatum uses them as a trojan horse for dissemination into other tissues. Subsequently, the yeast can induce host cell death, allowing them to migrate to another phagocyte. […] Dendritic cells provide the link between the innate and adaptive immune responses by acting as antigen-presenting cells. Human dendritic cells drive CD4+ and/or CD8+ T cell proliferation, which in turn can either clear the pathogen or lead to granuloma formation. CD4+ T cell polarization into Th1 phenotype leads to production of IFN-γ and TNF-α, which activates intracellular killing and is pivotal for control of the infection.

• #25 Overview of Histoplasmosis | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/1215/p2247.html

  When spores produced by the mycelial form of H. capsulatum become airborne, they are inhaled and deposited in alveoli. At normal body temperature (37C [98.6F]), the spores germinate into the yeast form of this dimorphic fungus and are ingested by pulmonary macrophages. The yeasts become parasitic, multiply within these cells, and travel to hilar and mediastinal lymph nodes, where they gain access to the blood circulation that disseminates them to various organs. Macrophages throughout the reticuloendothelial system ingest and sequester the organism. […] About 10 to 14 days after exposure, cellular immunity develops, and macrophages become fungicidal and clear an immunocompetent host of infection. Necrosis develops at the sites of infection in the lungs, lymph nodes, liver, spleen, and bone marrow, leading to caseation, fibrous encapsulation, calcium deposition and, within a few years of the primary infection, calcified granulomas. Any defects in cellular immunity result in a progressive disseminated form of infection that can be lethal.

• #26 Histoplasmosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Histoplasmosis_pathophysiology

  The release of cytokines activates macrophages, inhibiting the growth of the fungus and limit its spread to the surrounding tissue. This results in the formation of a granuloma where in the fungus is present in a nonviable state for life. […] In patients with immunosuppression, they are unable to mount an adequate T-cell mediated immune response resulting in uncontrolled growth of the organism with spread to the surrounding tissue and increasing the morbidity and mortality of the infection.

• #27 Histoplasmosis: Causes, Symptoms, Diagnosis & Treatment

  https://my.clevelandclinic.org/health/diseases/24811-histoplasmosis

  The fungus H. capsulatum gets into your lungs when you breathe it in from the soil. There, it enters your white blood cells and changes from a mold into its infectious form as a yeast. In most people, your immune cells destroy it, or wall it off from your body with granulomas, before you ever notice any symptoms. In certain circumstances, it can make you sick: […] If you have a compromised immune system, it can use your immune cells to spread to other parts of your body. This can cause life-threatening complications. […] If left untreated, it sometimes can spread to other parts of your body, especially if your immune system isn’t working as it should. It can cause lung damage in people with underlying lung disease.

• #28

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  H. capsulatum yeast cells are highly adapted to the mammalian host as they can effectively survive within intracellular niches in select phagocytic cells. […] Once Histoplasma enters the host, it must evade immune-mediated and intracellular defenses, and find a favorable niche for growth and reproduction, which may include dissemination and the development of a state of latency within granulomas. […] The pathogens ability to evade inflammatory responses and the intensity of the host immune response determine the severity of symptoms and clinical presentation, and whether a state of latency develops with the potential for reactivation. […] The yeast is the pathogenic form of H. capsulatum causing acute disease, or it can become latent, able to potentially reemerge in the setting of immunosuppression. However, H. capsulatum has many obstacles to overcome to cause host injury. It must bypass mucosal barriers during acute inoculation, evade host immune cell responses, and find its niche within host macrophages.

• #29

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  The entire mechanism of fungistasis by these proteins has not been fully elucidated. […] The pathogen needs to be able to utilize what is present or produce its own nutrients to meet its metabolic needs. […] H. capsulatum, by utilizing the previously discussed interactions with the host macrophage, can thrive in its intracellular niche. However, for infection to be propagated in the host and disseminate to other organs in the body, the pathogen needs to induce apoptosis of or otherwise leave the macrophage and infect subsequent phagocytes. […] The adaptive immune response once effectively activated can either clear the organism or lead to granuloma formation. If the latter occurs, there is the potential for reactivation of the organism. Reactivation is a response to impaired immunity.

• #30 Histoplasmosis: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/299054-overview

  Approximately 85-90% of individuals who are immunocompetent produce a positive response to skin antigen test for Histoplasma species. […] Clinical manifestations of histoplasmosis appear with continued exposure to large inocula. The initial pulmonary infection may disseminate systemically, with hematogenous spread, and produce extrapulmonary manifestations. […] Hematogenous spread to regional lymph nodes may occur through the lymphatics or the liver and spleen. […] Progressive disseminated histoplasmosis is rare in adult hosts who are immunocompetent. Systemic spread usually occurs in patients with impaired cellular immunity and typically involves the CNS, liver, spleen, and rheumatologic, ocular, and hematologic systems.

• #31 Histoplasmosis: An Overview Treatment of Histoplasmosis | IntechOpen

  https://www.intechopen.com/online-first/86238

  The spectrum of disease ranges from asymptomatic patients to severe, life-threatening disseminated disease, especially in immunocompromised individuals. The population at risk of developing clinically significant histoplasmosis has grown substantially with patients treated with an ever-expanding variety of immunosuppressive medications and/or with immunosuppressive medical conditions. […] In immunocompromised patients, the disease can occur due to primary infection, reinfection, or dissemination of latent foci persisting after remote infection. If reactivation occurs, a large population of immunosuppressed persons would be at risk. Reactivation of latent infections may complicate recipients of solid organ transplants and patients receiving immunosuppressive therapy for other reasons. […] Histoplasmosis in the immunocompromised host has some particularities. One of the more severe forms of the disease, disseminated histoplasmosis, is a progressive extrapulmonary infection often seen in immunocompromised patients (e.g., AIDS, those on immunosuppressive medications, etc.) or at extremes of age.

• #32 Pathogenesis and clinical manifestations of disseminated histoplasmosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis/print

  In patients with disseminated infection, macrophages are typically engorged with yeasts, supporting the important role of intracellular proliferation of the organism. Organisms are confined to macrophages but less commonly can be seen within the tissue spaces as well as in peripheral white blood cells. […] T cell immunity plays the predominant role in recovery from histoplasmosis. Once cellular immunity to Histoplasma develops, macrophages become activated to kill the organism. Cytokines including interleukin (IL)-12 and interferon (IFN)-gamma trigger macrophages to kill the fungus and halt progression of disease.

• #33 Histoplasmosis: An Overview Treatment of Histoplasmosis | IntechOpen

  https://www.intechopen.com/online-first/86238

  The spectrum of disease ranges from asymptomatic patients to severe, life-threatening disseminated disease, especially in immunocompromised individuals. The population at risk of developing clinically significant histoplasmosis has grown substantially with patients treated with an ever-expanding variety of immunosuppressive medications and/or with immunosuppressive medical conditions. […] In immunocompromised patients, the disease can occur due to primary infection, reinfection, or dissemination of latent foci persisting after remote infection. If reactivation occurs, a large population of immunosuppressed persons would be at risk. Reactivation of latent infections may complicate recipients of solid organ transplants and patients receiving immunosuppressive therapy for other reasons. […] Histoplasmosis in the immunocompromised host has some particularities. One of the more severe forms of the disease, disseminated histoplasmosis, is a progressive extrapulmonary infection often seen in immunocompromised patients (e.g., AIDS, those on immunosuppressive medications, etc.) or at extremes of age.

• #34 Histoplasmosis: Cause, Types & Complications

  https://www.healthline.com/health/histoplasmosis

  Widespread disease usually occurs in people with impaired immune systems. In areas where the fungus is common, the CDC says that it may occur in up to 30 percent of people with HIV. […] Histoplasmosis can also cause a number of complications. […] Histoplasmosis can cause a serious condition called meningitis. Meningitis occurs when the membranes surrounding your brain and spinal cord become infected. […] Infection can damage your adrenal glands and this may cause problems with hormone production.

• #35 Histoplasmosis: An Overview Treatment of Histoplasmosis | IntechOpen

  https://www.intechopen.com/online-first/86238

  The spectrum of disease ranges from asymptomatic patients to severe, life-threatening disseminated disease, especially in immunocompromised individuals. The population at risk of developing clinically significant histoplasmosis has grown substantially with patients treated with an ever-expanding variety of immunosuppressive medications and/or with immunosuppressive medical conditions. […] In immunocompromised patients, the disease can occur due to primary infection, reinfection, or dissemination of latent foci persisting after remote infection. If reactivation occurs, a large population of immunosuppressed persons would be at risk. Reactivation of latent infections may complicate recipients of solid organ transplants and patients receiving immunosuppressive therapy for other reasons. […] Histoplasmosis in the immunocompromised host has some particularities. One of the more severe forms of the disease, disseminated histoplasmosis, is a progressive extrapulmonary infection often seen in immunocompromised patients (e.g., AIDS, those on immunosuppressive medications, etc.) or at extremes of age.

• #36 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The tuberculoid form usually corresponds to a low inoculation and effective tissue response of the host. The tissue shows an inflammatory infiltrate rich in activated macrophages and lymphocytes mostly of T-helper CD4+ phenotype progressively recruited in vivo. Granulomas with epithelioid cells with/without giant cells can also be observed. The evolution of this form, by analogy with tuberculosis, is caseous necrosis. Here, the histoplasmas are usually few in number and are located in the cytoplasm of histiocytes (intracellular). […] The anergic form is observed in HIV patients and shows little or no tissue response. Local macrophages remain inactive. The typical appearance is that of an abundance of intracellular and extracellular yeast. […] The mixed form represents an intermediate form between the tuberculoid form and the anergic form. Finally, in the sequelae form, the scarring fibrosis predominates and the inflammation is mild. In this form, rare yeasts can be found that can correspond to a relapse case or eventual reactivation.

• #37 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The tuberculoid form was the most common histological form found across all organs. This granulomatous form is found in both immunocompetent and immunocompromised patients. Nevertheless, the typical tuberculoid appearance associating both well-formed epithelioid granulomas and multinucleated giant cells with or without caseous necrosis was not so frequent, a finding that has already been highlighted by previous studies performed only on digestive and hepatic histoplasmosis (Lamps et al., 2000). Granulomas are strongly associated with a high fungal load, which easily leads to diagnosis. However, low fungal loads with <1 H. capsulatum yeast per microscopic field ×400, without any real inflammatory infiltrate, are not uncommon and should be diagnosed using the Gomori-Grocott stain, an oil lens with a higher magnification (×1,000) to avoid confusion with other fungal yeasts.

• #38 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The tuberculoid form usually corresponds to a low inoculation and effective tissue response of the host. The tissue shows an inflammatory infiltrate rich in activated macrophages and lymphocytes mostly of T-helper CD4+ phenotype progressively recruited in vivo. Granulomas with epithelioid cells with/without giant cells can also be observed. The evolution of this form, by analogy with tuberculosis, is caseous necrosis. Here, the histoplasmas are usually few in number and are located in the cytoplasm of histiocytes (intracellular). […] The anergic form is observed in HIV patients and shows little or no tissue response. Local macrophages remain inactive. The typical appearance is that of an abundance of intracellular and extracellular yeast. […] The mixed form represents an intermediate form between the tuberculoid form and the anergic form. Finally, in the sequelae form, the scarring fibrosis predominates and the inflammation is mild. In this form, rare yeasts can be found that can correspond to a relapse case or eventual reactivation.

• #39 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The tuberculoid form usually corresponds to a low inoculation and effective tissue response of the host. The tissue shows an inflammatory infiltrate rich in activated macrophages and lymphocytes mostly of T-helper CD4+ phenotype progressively recruited in vivo. Granulomas with epithelioid cells with/without giant cells can also be observed. The evolution of this form, by analogy with tuberculosis, is caseous necrosis. Here, the histoplasmas are usually few in number and are located in the cytoplasm of histiocytes (intracellular). […] The anergic form is observed in HIV patients and shows little or no tissue response. Local macrophages remain inactive. The typical appearance is that of an abundance of intracellular and extracellular yeast. […] The mixed form represents an intermediate form between the tuberculoid form and the anergic form. Finally, in the sequelae form, the scarring fibrosis predominates and the inflammation is mild. In this form, rare yeasts can be found that can correspond to a relapse case or eventual reactivation.

• #40 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The tuberculoid form usually corresponds to a low inoculation and effective tissue response of the host. The tissue shows an inflammatory infiltrate rich in activated macrophages and lymphocytes mostly of T-helper CD4+ phenotype progressively recruited in vivo. Granulomas with epithelioid cells with/without giant cells can also be observed. The evolution of this form, by analogy with tuberculosis, is caseous necrosis. Here, the histoplasmas are usually few in number and are located in the cytoplasm of histiocytes (intracellular). […] The anergic form is observed in HIV patients and shows little or no tissue response. Local macrophages remain inactive. The typical appearance is that of an abundance of intracellular and extracellular yeast. […] The mixed form represents an intermediate form between the tuberculoid form and the anergic form. Finally, in the sequelae form, the scarring fibrosis predominates and the inflammation is mild. In this form, rare yeasts can be found that can correspond to a relapse case or eventual reactivation.

• #41 Histoplasmosis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/histoplasmosis/symptoms-causes/syc-20373495

  Histoplasmosis is caused by the reproductive cells (spores) of the fungus Histoplasma capsulatum. They float into the air when dirt or other material is disturbed. […] The fungus thrives in damp soil that’s rich in organic material, especially the droppings from birds and bats. It’s particularly common in chicken and pigeon coops, old barns, caves, and parks. […] Histoplasmosis can cause many serious complications, even in otherwise healthy people. For infants, older adults and people with weakened immune systems, the potential problems are often life-threatening. […] Complications can include: Acute respiratory distress syndrome. Histoplasmosis can damage lungs to the point that the air sacs begin filling with fluid. This prevents good air exchange and can deplete the oxygen in your blood. […] Adrenal insufficiency. Histoplasmosis can harm your adrenal glands, which produce hormones that give instructions to virtually every organ and tissue in your body.

• #42 Histoplasmosis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/histoplasmosis/symptoms-causes/syc-20373495

  Histoplasmosis is caused by the reproductive cells (spores) of the fungus Histoplasma capsulatum. They float into the air when dirt or other material is disturbed. […] The fungus thrives in damp soil that’s rich in organic material, especially the droppings from birds and bats. It’s particularly common in chicken and pigeon coops, old barns, caves, and parks. […] Histoplasmosis can cause many serious complications, even in otherwise healthy people. For infants, older adults and people with weakened immune systems, the potential problems are often life-threatening. […] Complications can include: Acute respiratory distress syndrome. Histoplasmosis can damage lungs to the point that the air sacs begin filling with fluid. This prevents good air exchange and can deplete the oxygen in your blood. […] Adrenal insufficiency. Histoplasmosis can harm your adrenal glands, which produce hormones that give instructions to virtually every organ and tissue in your body.

• #43 Histoplasmosis – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/histoplasmosis/symptoms-causes/syc-20373495

  Histoplasmosis is caused by the reproductive cells (spores) of the fungus Histoplasma capsulatum. They float into the air when dirt or other material is disturbed. […] The fungus thrives in damp soil that’s rich in organic material, especially the droppings from birds and bats. It’s particularly common in chicken and pigeon coops, old barns, caves, and parks. […] Histoplasmosis can cause many serious complications, even in otherwise healthy people. For infants, older adults and people with weakened immune systems, the potential problems are often life-threatening. […] Complications can include: Acute respiratory distress syndrome. Histoplasmosis can damage lungs to the point that the air sacs begin filling with fluid. This prevents good air exchange and can deplete the oxygen in your blood. […] Adrenal insufficiency. Histoplasmosis can harm your adrenal glands, which produce hormones that give instructions to virtually every organ and tissue in your body.

• #44 Histoplasmosis: Cause, Types & Complications

  https://www.healthline.com/health/histoplasmosis

  Widespread disease usually occurs in people with impaired immune systems. In areas where the fungus is common, the CDC says that it may occur in up to 30 percent of people with HIV. […] Histoplasmosis can also cause a number of complications. […] Histoplasmosis can cause a serious condition called meningitis. Meningitis occurs when the membranes surrounding your brain and spinal cord become infected. […] Infection can damage your adrenal glands and this may cause problems with hormone production.

• #45 Histoplasmosis: Cause, Types & Complications

  https://www.healthline.com/health/histoplasmosis

  Widespread disease usually occurs in people with impaired immune systems. In areas where the fungus is common, the CDC says that it may occur in up to 30 percent of people with HIV. […] Histoplasmosis can also cause a number of complications. […] Histoplasmosis can cause a serious condition called meningitis. Meningitis occurs when the membranes surrounding your brain and spinal cord become infected. […] Infection can damage your adrenal glands and this may cause problems with hormone production.

• #46 Frontiers | Cytological and Histopathological Spectrum of Histoplasmosis: 15 Years of Experience in French Guiana

  https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.591974/full

  The severity of disease after inhalation of H. capsulatum varies, with the intensity of exposure and the host’s immunity. This may lead to asymptomatic infections or mild pulmonary disease for low-intensity exposures in immunocompetent individuals, whereas heavy exposures may lead to severe pulmonary infections. Among patients with underlying lung disease, a chronic lung infection may develop with gradual loss of pulmonary function, and if untreated, frequent death. Among immunocompromised patients the infection progressively disseminates to other organs leading to non-specific syndromes. Various organs such as the lungs, gastrointestinal tract, liver or lymph nodes may thus be involved in the same patient. Immunocompromised patients infected with Histoplasma are 10 to 15 times more likely to develop a disseminated form of the disease, which is invariably fatal if left untreated.

• #47 Pathogenicity & virulence of Histoplasma capsulatum – A multifaceted organism adapted to intracellular environments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9621017/

  Histoplasmosis is a systemic mycosis caused by the thermally dimorphic fungus Histoplasma capsulatum. […] In this review, we discuss the established virulence factors and pathogenesis traits that make H. capsulatum highly adapted to a wide variety of hosts, including mammals. Understanding and integrating these mechanisms is a key step toward devising new preventative and therapeutic interventions. […] The onset of infection occurs through the inhalation of microconidia or mycelial fragments by the host. This step is followed by the deposition of fungal propagules into the pulmonary alveoli and a rapid conversion to the yeast morphology, triggered by the fungal response to the temperature switch. H. capsulatum yeasts have an optimal growth at 37 C. Morphological changes can occur even before microconidia reach the lungs or within the intracellular environment.

• #48

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7212190/

  The interactions of the adaptive and innate immune response, eventual granuloma formation and potential reactivation are each complex and interconnected connected processes. However, further characterization and definitions of the elements involved are beneficial as this can lead to therapeutic targets against disease.

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