학술논문
Immunogenetics associated with severe coccidioidomycosis
Document Type
article
Author
Amy P. Hsu; Agnieszka Korzeniowska; Cynthia C. Aguilar; Jingwen Gu; Eric Karlins; Andrew J. Oler; Gang Chen; Glennys V. Reynoso; Joie Davis; Alexandria Chaput; Tao Peng; Ling Sun; Justin B. Lack; Derek J. Bays; Ethan R. Stewart; Sarah E. Waldman; Daniel A. Powell; Fariba M. Donovan; Jigar V. Desai; Nima Pouladi; Debra A. Long Priel; Daisuke Yamanaka; Sergio D. Rosenzweig; Julie E. Niemela; Jennifer Stoddard; Alexandra F. Freeman; Christa S. Zerbe; Douglas B. Kuhns; Yves A. Lussier; Kenneth N. Olivier; Richard C. Boucher; Heather D. Hickman; Jeffrey Frelinger; Joshua Fierer; Lisa F. Shubitz; Thomas L. Leto; George R. Thompson III; John N. Galgiani; Michail S. Lionakis; Steven M. Holland
Source
JCI Insight, Vol 7, Iss 22 (2022)
Subject
Language
English
ISSN
2379-3708
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, 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.