Coccidioidomycosis: Factors Affecting the Host-Parasite Interaction

Drutz, David J.; Huppert, M.

doi:10.1093/infdis/147.3.372

Cited by 143 publications

(101 citation statements)

References 31 publications

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“…In spite of this intense phagocytic response to endosporulation, rarely are the endospores observed within the host cells. Earlier in vitro studies of host phagocyte interaction with Coccidioides have indicated that macrophages and neutrophils are only able to partially inhibit growth of the pathogen; they are unable to kill the organism (2,16,19). We speculated that opsonization of SOWgp-coated endospores produced by the ⌬mep1 mutant strain would result in increased phagocytosis and clearance of the pathogen from infected host tissue.…”

Section: Discussionmentioning

confidence: 98%

A Metalloproteinase of Coccidioides posadasii Contributes to Evasion of Host Detection

et al. 2005

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Coccidioides posadasii is a fungal respiratory pathogen of humans that can cause disease in immunocompetent individuals. Coccidioidomycosis ranges from a mild to a severe infection. It is frequently characterized either as a persistent disease that requires months to resolve or as an essentially asymptomatic infection that can reactivate several years after the original insult. In this report we describe a mechanism by which the pathogen evades host detection during the pivotal reproductive (endosporulation) phase of the parasitic cycle. A metalloproteinase (Mep1) secreted during endospore differentiation digests an immunodominant cell surface antigen (SOWgp) and prevents host recognition of endospores during the phase of development when these fungal cells are most vulnerable to phagocytic cell defenses. C57BL/6 mice were immunized with recombinant SOWgp and then challenged with a mutant strain of C. posadasii in which the MEP1 gene was disrupted. The animals showed a significant increase in percent survival compared to SOWgp-immune mice challenged with the parental strain. To explain these results, we proposed that retention of SOWgp on the surfaces of endospores of the mutant strain in the presence of high titers of antibody to the immunodominant antigen contributes to opsonization, increased phagocytosis, and killing of the fungal cells. In vitro studies of the interaction between a murine alveolar macrophage cell line and parasitic cells coated with SOWgp showed that the addition of anti-SOWgp antibody could enhance phagocytosis and killing of Coccidioides. We suggest that Mep1 plays a pivotal role as a pathogenicity determinant during coccidioidal infections and contributes to the ability of the pathogen to persist within the mammalian host.

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Section: Discussionmentioning

confidence: 98%

A Metalloproteinase of Coccidioides posadasii Contributes to Evasion of Host Detection

et al. 2005

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“…One exception to this observation is in women during pregnancy, where the risk of severe, symptomatic coccidioidomycosis is high and increases the later during pregnancy that infection occurs (122). While it has been presumed that suppression of cellular immunity associated with pregnancy is the major cause for this increased risk, Drutz and coworkers have suggested that hormonal changes that occur during gestation may increase the growth of the fungus and lead to more severe clinical illness (123,124).…”

Section: Characteristics Associated With Symptomatic Coccidioidomycosmentioning

confidence: 99%

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

et al. 2013

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SUMMARY Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii . This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

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“…However, the precise mechanisms whereby macrophages interact with spherules and endospores are not completely understood. In vitro studies suggest that spherules may escape phagocytosis by macrophages (8). Adaptive immunity to Coccidioides has been extensively studied, and it involves primarily CD4 ϩ T lymphocytes.…”

mentioning

confidence: 99%

Innate Immunity to the Pathogenic Fungus Coccidioides posadasii Is Dependent on Toll-Like Receptor 2 and Dectin-1

et al. 2005

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Coccidioides posadasii is a pathogenic fungus that causes endemic and epidemic coccidioidomycosis in the deserts of North, Central, and South America. How the innate immune system responds to the organism is not well understood. Here we show that elicited mouse peritoneal macrophages respond to spherules (the tissue form of the fungus) by producing proinflammatory cytokines as measured by quantitative PCR of cellular transcripts and by enzyme-linked immunosorbent assay (ELISA) assays for secreted protein. We examined the contribution of Toll-like receptors (TLR) and MyD88 in macrophage responses to formalin-killed spherules (FKS) by comparing cytokine responses of elicited macrophages from different knockout mice. FKS were added to elicited mouse peritoneal macrophages from wild-type, TLR2؊/؊ , and MyD88 ؊/؊ cells, and wild-type cells made more tumor necrosis factor alpha, MIP-2, and interleukin 6 than did the mutant macrophages. In contrast, the C3H/HeJ mice, which have a point mutation in TLR4, and TLR4 ؊/؊ B6 mice exhibited no defect in cytokine production compared to the control mice. We also investigated the role of the macrophage ␤-glucan receptor, Dectin-1. RAW 264.7 macrophages overexpressing Dectin-1 produced more cytokines in respond to FKS, live spherules, and purified ␤-glucan than did control RAW cells. Blockage of Dectin-1 with antibodies inhibited cytokine production in elicited mouse peritoneal macrophages. Taken together, these results show that cytokine responses in mouse peritoneal macrophages to C. posadasii spherules are dependent on TLR2, MyD88, and Dectin-1.

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Coccidioidomycosis: Factors Affecting the Host-Parasite Interaction

Cited by 143 publications

References 31 publications

A Metalloproteinase of Coccidioides posadasii Contributes to Evasion of Host Detection

A Metalloproteinase of Coccidioides posadasii Contributes to Evasion of Host Detection

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

Innate Immunity to the Pathogenic Fungus Coccidioides posadasii Is Dependent on Toll-Like Receptor 2 and Dectin-1

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