B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

Allen, Holly L.; Deepe, George S.

doi:10.4049/jimmunol.177.3.1763

Cited by 33 publications

(33 citation statements)

References 49 publications

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“…Sublethal infection was induced by anesthetization and intranasal inoculation of H. capsulatum cells. Determinations of colony- 6 5 ϫ 10 forming units, cytokine levels, and antibody production and histological analyses were performed as described elsewhere [23]. Lethal infection was performed by intranasal inoculation with H. capsulatum cells.…”

Section: Fungusmentioning

confidence: 99%

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Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Martinez¹,

Mihu²,

Gácser³

et al. 2009

J INFECT DIS

102

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The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-1 receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.

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Section: Fungusmentioning

confidence: 99%

“…On induction of cell-mediated immunity and the production of cytokines, macrophages are activated, and the fungus is eliminated. Although B celldeficient animals experienced an accelerated progression to death in the case of reactivation disease [6], B cells are less critical in primary histoplasmosis [3].…”

mentioning

confidence: 99%

Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Martinez¹,

Mihu²,

Gácser³

et al. 2009

J INFECT DIS

102

View full text Add to dashboard Cite

show abstract

“…Upon induction of cell-mediated immunity and the production of cytokines, macrophages are activated, and the fungus is eliminated. The importance of B cells in primary histoplasmosis is less critical (3), however, in B celldeficient animals the progression toward lethal infection is accelerated in reactivation disease (6).…”

mentioning

confidence: 99%

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungusHistoplasma capsulatum

Lázár‐Molnár

Gácser²,

Freeman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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The PD-1 costimulatory receptor inhibits T cell receptor signaling upon interacting with its ligands PD-L1 and PD-L2. The PD-1/PD-L pathway is critical in maintaining self-tolerance. In this study, we examined the role of PD-1 in a mouse model of acute infection with Histoplasma capsulatum, a major human pathogenic fungus. In a lethal model of histoplasmosis, all PD-1-deficient mice survived infection, whereas the wild-type mice died with disseminated disease. PD-L expression on macrophages and splenocytes was up-regulated during infection, and macrophages from infected mice inhibited in vitro T cell activation. Of interest, antibody blocking of PD-1 significantly increased survival of lethally infected wild-type mice. Thus, our studies extend the role of the PD-1/PD-L pathway in regulating antimicrobial immunity to fungal pathogens. The results show that the PD-1/PD-L pathway has a key role in the regulation of antifungal immunity, and suggest that manipulation of this pathway represents a strategy of immunotherapy for histoplasmosis.costimulation ͉ fungal infection ͉ programmed death-1

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“…B cells are critical to limiting secondary histoplasmosis (22), but our data suggest that they have little influence in primary infections. The B6.129S2-Igh6 tm1cgn (Igh6 −/− ; previously μMT) mouse strain lacks conventional B cells, due to disruption of the IgM gene; however, it manifests an increase in neutrophil migration during infection and is more resistant to Leishmania infection than wild type controls (23).…”

Section: Resultsmentioning

confidence: 50%

Genetic control of immune cell types in fungal disease

Mayfield

Fontana

Rine

2010

Proc. Natl. Acad. Sci. U.S.A.

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Millions of people harbor latent infections of the fungus Histoplasma capsulatum. Such persistent infections represent a stalemate between mechanisms of virulence and the immune response. The differing responses of inbred mouse strains to the same pathogen reflect variation in the genes that control the outcome of infection. Here we show that a 250-fold difference in H. capsulatum susceptibility between inbred mouse strains is attributable to the genotype at the MHC H2 locus. Gene expression analysis of strains varying only at the H2 locus identified genotype-specific and genotype-independent expression signatures, including infection-induced genes such as the fungal pattern recognition receptor Clec7a. Surprisingly, B-cell-specific gene expression was negatively correlated with fungal burden, whereas neutrophil-specific genes were correlated with superior disease outcome. Indeed, disease outcome improved when B cells were eliminated and neutrophils were more active, a previously unknown aspect of the host response. These data refine the understanding of genetic influences on histoplasmosis, reveal how shifts in the composition of immune cell populations compel different disease outcomes, and uncover how innate immunity modulation alters histoplasmosis.G enetic differences among individuals can have profound effects on infectious disease susceptibility and severity; for example, severe infections with the dimorphic fungal pathogen Coccidioides immitis are more frequent in males and people of African or Asian descent (1). This relationship inspires the hope that uncovering the pivotal genes affecting disease outcome might lead to new therapeutic strategies for controlling disease. For histoplasmosis, a fungal pneumonia affecting millions of people worldwide (2), infection outcomes vary greatly among mouse strains with only minor differences in cytokine profiles (3, 4). Although molecular ablation has connected an orderly and well-defined cytokine response to histoplasmosis outcome (5-7), previous mouse strain studies have highlighted the unexplained aspects of a successful immune response. The experiments reported herein identify a major influence of the H2 locus on experimental infections of mice with the fungal pathogen Histoplasma capsulatum, uncover gene expression signatures of neutrophils and B cells in resistant strains of mice, show that B cells impair the antifungal response, and implicate the innate immune system as an early control point. ResultsGenetic Control of Disease Outcome After H. capsulatum Infection.We previously mapped quantitative trait loci controlling the phenotype of fungal burden using recombinant inbred mice (3). These data identify two regions on chromosome 17 linked to 250-fold lower fungal burden in the spleens of resistant A/J mice compared with sensitive C57BL/6 (B6) mice. One of those regions is tightly linked to the MHC H2, a highly variable multigene complex encoding the proteins responsible for antigen presentation. To test the contribution of the H2 locus to the immune respon...

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B Cells and CD4−CD8− T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis

Cited by 33 publications

References 49 publications

Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

Methamphetamine Enhances Histoplasmosis by Immunosuppression of the Host

The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungusHistoplasma capsulatum

Genetic control of immune cell types in fungal disease

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