Immunogenetics associated with severe coccidioidomycosis

Abstract

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the Southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, <1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled DCM patients and performed whole-exome sequencing. In an exploratory set of 67 DCM patients, two had haploinsufficient STAT3 mutations, while defects in b-glucan sensing and response were seen in 34/67 (50.7%) cases. Damaging CLEC7A (n=14) and PLCG2 (n=11) variants were associated with impaired production of b-glucan-stimulated TNF-a from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired b-glucan sensing or response affecting TNF-a and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis

“…Whether genetic variation in the CLR/CARD9 pathway may explain, at least partly, the increased prevalence of subcutaneous mycoses in certain subtropical regions warrants investigation. Our findings, together with the accompanying report by Hsu and colleagues ( 53 ), imply that Dectin-1 may be critical to the optimal development of antifungal defense following traumatic inoculation by low-virulence, dematiaceous fungi ( Corynespora ), or inhalational exposure to highly virulent fungi in certain geographic areas ( Coccidioides ).…”

Immune responses to human fungal pathogens and therapeutic prospects

“…In line with this crucial role of granulomatous inflammation, inborn errors of immunity affecting type 1 immune responses caused by mutations in the genes encoding IL-12RB1, IFNγR1, STAT1, STAT3, CD40L or GATA2 (Table 2 and Supplementary Table 2 ) predispose to severe, disseminated infections by these fungi, as do neutralizing autoantibodies to IFNγ 121 and receipt of TNF inhibitors, JAK–STAT inhibitors or the IFNγ-targeted biologic emapalumab 9 (Table 3 and Supplementary Table 3 ). In Coccidioides -infected patients, genetic variants in β-glucan sensing and response genes (for example, CLEC7A and PLCG2 ) that impair TNF production were recently shown to underlie disseminated disease in ~50% of evaluated patients 143 . By contrast, type 2 immune responses are detrimental for pathogen control by dampening type 1 responses and skewing macrophages towards a phenotype that is permissive for intracellular fungal persistence 144 .…”

Advocating for Coccidioidomycosis to Be a Reportable Disease Nationwide in the United States and Encouraging Disease Surveillance across North and South America

“…Human genetic variations can contribute to high incidence rates of disseminated disease among specific populations, such as African Americans, Asian/Pacific Islanders, and Latinos, compared to European Americans [ 27 , 37 , 38 , 39 ]. Furthermore, allelic variations of immune factors of the IL-12-IFN-γ signaling, innate immune sensing, NFκB signaling, and IL-17 signaling molecules have been predicted to associate with the severity of coccidioidomycosis [ 40 , 41 ]. Altogether, those genetic correlation studies suggest that nationwide surveillance may facilitate the rapid identification of coccidioidomycosis patients with any at-risk conditions.…”