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