The Known Unknowns of the Immune Response to Coccidioides.

Coccidioidomycosis, otherwise known as Valley Fever, is caused by the dimorphic fungi Coccidioides immitis and C. posadasii. While most clinical cases present with self-limiting pulmonary infection, dissemination of Coccidioides spp. results in prolonged treatment and portends higher mortality rates. While the structure, genome, and niches for Coccidioides have provided some insight into the pathogenesis of disease, the underlying immunological mechanisms of clearance or inability to contain the infection in the lung are poorly understood. This review focuses on the known innate and adaptive immune responses to Coccidioides and highlights three important areas of uncertainty and potential approaches to address them. Closing these gaps in knowledge may enable new preventative and therapeutic strategies to be pursued.

Myeloid C-type lectin receptors that recognize fungal mannans interact with Pneumocystis organisms and major surface glycoprotein.

Myeloid C-type lectin receptors (CLRs) are innate immune recognition molecules that bind to microorganisms via their carbohydrate recognition domains. In this study, we utilized a library of CLRs that recognize fungal mannans. We used this library to screen against Pneumocystis carinii (Pc) homogenates or purified Pc major surface glycoprotein (Msg) present on Pneumocystis. The results demonstrated that all of the mammalian CLR hFc-fusions tested displayed significant interaction/binding with Pc organisms, and furthermore to isolated Msg. Highest Pc organism and Msg binding activities were with CLR members Mincle, Dectin-2, DC-SIGN and MCL. An immunofluorescence assay with the respective CLR hFc-fusions against whole Pc life forms corroborated these findings. Although some of these CLRs have been implicated previously as important for Pneumocystis pathogenesis (Dectin-1/Dectin-2/Mincle), this is the first analysis of head-to-head comparison of known fungal mannan binding CLR-hFc fusions with Pc. Lastly, heat treatment resulted in reducted CLR binding.

Investigation of Genetic Susceptibility to Blastomycosis Reveals Interleukin-6 as a Potential Susceptibility Locus.

Genetic differences are hypothesized to underlie ethnic disparities in incidence rates of the endemic systemic mycoses, including blastomycosis. Individuals of Hmong ancestry display elevated risk for this serious fungal infection. Here, we interrogated the genomes of Wisconsin (WI) Hmong blastomycosis patients using homozygosity mapping to uncover regions of the genome that are likely shared among the greater Hmong population and filtered for variants with high potential to affect disease susceptibility. This approach uncovered 113 candidate susceptibility variants, and among the most promising are those in genes involved in the interleukin-17 (IL-17) response. In particular, we identified 25 linked variants near the gene encoding IL-6 (IL6). We validated differences in cytokine production between Hmong and European volunteers and formally demonstrated a critical role for IL-6 in the development of adaptive immunity to Blastomyces dermatitidis Our findings suggest that the dysregulation of IL-17 responses underlies a recently reported and poorly understood ethnic health disparity.IMPORTANCE Blastomycosis is a potentially life-threatening infection caused by the fungus Blastomyces dermatitidis As with related fungal diseases, blastomycosis is noted to affect some populations more than others. These patterns of illness are often not related to predisposing conditions or exposure risks; thus, genetic differences are thought to underlie these health disparities. People of Hmong ancestry in Wisconsin are at elevated risk of blastomycosis compared to the general population. We studied the genetic codes of Hmong blastomycosis patients and identified candidate sites in their genomes that may explain their susceptibility to this infection. We further studied one particular region of the genome that is involved with the immune processes that fight B. dermatitidis Our work revealed population differences in the response to fungi. A better understanding of the genetic underpinnings of susceptibility to infectious diseases has broader implications for community health, especially in the paradigm of personalized medicine.

CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology.

The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1ß and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1ß and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRγ-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs.