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Immunogenetics associated with severe coccidioidomycosis. 2022
Amy P Hsu, and
Agnieszka Korzeniowska, and
Cynthia C Aguilar, and
Jingwen Gu, and
Eric Karlins, and
Andrew J Oler, and
Gang Chen, and
Glennys V Reynoso, and
Joie Davis, and
Alexandria Chaput, and
Tao Peng, and
Ling Sun, and
Justin B Lack, and
Derek J Bays, and
Ethan R Stewart, and
Sarah E Waldman, and
Daniel A Powell, and
Fariba M Donovan, and
Jigar V Desai, and
Nima Pouladi, and
Debra A Long Priel, and
Daisuke Yamanaka, and
Sergio D Rosenzweig, and
Julie E Niemela, and
Jennifer Stoddard, and
Alexandra F Freeman, and
Christa S Zerbe, and
Douglas B Kuhns, and
Yves A Lussier, and
Kenneth N Olivier, and
Richard C Boucher, and
Heather D Hickman, and
Jeffrey Frelinger, and
Joshua Fierer, and
Lisa F Shubitz, and
Thomas L Leto, and
George R Thompson, and
John N Galgiani, and
Michail S Lionakis, and
Steven M Holland
Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
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.
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