Immunogenetics associated with severe coccidioidomycosis

JCI Insight. 2022 Nov 22;7(22):e159491. doi: 10.1172/jci.insight.159491.


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, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Keywords: Fungal infections; Genetics; Infectious disease; Innate immunity; Population genetics.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Coccidioides / genetics
  • Coccidioidomycosis* / epidemiology
  • Coccidioidomycosis* / genetics
  • Coccidioidomycosis* / microbiology
  • Humans
  • Hydrogen Peroxide
  • Tumor Necrosis Factor-alpha / genetics
  • beta-Glucans*


  • Tumor Necrosis Factor-alpha
  • Hydrogen Peroxide
  • beta-Glucans