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Immunogenetics associated with severe coccidioidomycosis

  1. 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
    Long Priel, Debra A
    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 Iii, George R
    Galgiani, John N
    Lionakis, Michail S
    Holland, Steven M

  2. Author Address

    Laboratory of Clinical Immunology and Microbiology, NIAID/NIH, Bethesda, United States of America., Bioinformatics and Computational Biosciences Branch, NIAID/NIH, Bethesda, United States of America., Marsico Lung Institute and Cystic Fibrosis Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States of America., Valley Fever Center for Excellence, The University of Arizona, Tucson, United States of America., Frederick National Laboratory for Cancer Research, NIH, Frederick, United States of America., Department of Internal Medicine, University of California Davis Health, Sacramento, United States of America., Center for Biomedical Informatics and Biostatistics, The University of Arizona, Tucson, United States of America., Neutrophil Monitoring Laboratory, SAIC Frederick, Frederick, United States of America., Laboratory for Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan., Department of Laboratory Medicine, NIH, Bethesda, United States of America., Pulmonary Critical Medicine Section, National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America., Department of Immunology, The University of Arizona, Tucson, United States of America., University of California San Diego School of Medicine, San Diego, United States of America., Department of Medical Microbiology and Immunology, UC Davis, Davis, United States of America., Department of Medicine, The University of Arizona College of Medicine, Tucson, United States of America.,
    1. Year: 2022
    2. Date: Sep 27
    3. Epub Date: 2022 09 27
  2. Journal: JCI insight
    1. Pages: e159491
  4. Type of Article: Article
  1. 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, <1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled DCM patients and performed whole-exome sequencing. In an exploratory set of 67 DCM patients, two had haploinsufficient STAT3 mutations, while defects in ß-glucan sensing and response were seen in 34/67 (50.7%) cases. Damaging CLEC7A (n=14) and PLCG2 (n=11) variants were associated with impaired production of ß-glucan-stimulated TNF-a from peripheral blood mononuclear cells compared to healthy controls (P<0.005). Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were over-represented in DCM (P=0.0206, P=0.015, respectively) including CLEC7A Y238* (P=0.0105) and PLCG2 R268W (P=0.0025). A validation cohort of 111 DCM patients confirmed PLCG2 R268W (P=0.0276), CLEC7A I223S (P=0.044), and CLEC7A Y238* (P=0.0656). Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived H2O2 in transfected cells. Heterozygous DUOX1 or DUOXA1 variants which impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired ß-glucan sensing or response affecting TNF-a and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

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External Sources

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  2. DOI: 10.1172/jci.insight.159491
  3. PMID: 36166305
  4. PII : 159491

Library Notes

  1. Fiscal Year: FY2022-2023
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