%0 Journal Article
%T Immunogenetics associated with severe coccidioidomycosis.
%A Hsu AP
%A Korzeniowska A
%A Aguilar CC
%A Gu J
%A Karlins E
%A Oler AJ
%A Chen G
%A Reynoso GV
%A Davis J
%A Chaput A
%A Peng T
%A Sun L
%A Lack JB
%A Bays DJ
%A Stewart ER
%A Waldman SE
%A Powell DA
%A Donovan FM
%A Desai JV
%A Pouladi N
%A Long Priel DA
%A Yamanaka D
%A Rosenzweig SD
%A Niemela JE
%A Stoddard J
%A Freeman AF
%A Zerbe CS
%A Kuhns DB
%A Lussier YA
%A Olivier KN
%A Boucher RC
%A Hickman HD
%A Frelinger J
%A Fierer J
%A Shubitz LF
%A Leto TL
%A Thompson GR
%A Galgiani JN
%A Lionakis MS
%A Holland SM
%J JCI Insight
%V 7
%N 22
%D 11 2022 22
%M 36166305
%F 9.484
%R 10.1172/jci.insight.159491
%X 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.