Dataset Information

Immunogenetics associated with severe coccidioidomycosis.

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 β-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 β-glucan-stimulated TNF-α 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 β-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

SUBMITTER: Hsu AP

PROVIDER: S-EPMC9746810 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Immunogenetics associated with severe coccidioidomycosis.

Hsu Amy P AP Korzeniowska Agnieszka A Aguilar Cynthia C CC Gu Jingwen J Karlins Eric E Oler Andrew J AJ Chen Gang G Reynoso Glennys V GV Davis Joie J Chaput Alexandria A Peng Tao T Sun Ling L Lack Justin B JB Bays Derek J DJ Stewart Ethan R ER Waldman Sarah E SE Powell Daniel A DA Donovan Fariba M FM Desai Jigar V JV Pouladi Nima N Long Priel Debra A DA Yamanaka Daisuke D Rosenzweig Sergio D SD Niemela Julie E JE Stoddard Jennifer J Freeman Alexandra F AF Zerbe Christa S CS Kuhns Douglas B DB Lussier Yves A YA Olivier Kenneth N KN Boucher Richard C RC Hickman Heather D HD Frelinger Jeffrey J Fierer Joshua J Shubitz Lisa F LF Leto Thomas L TL Thompson George R GR Galgiani John N JN Lionakis Michail S MS Holland Steven M SM

JCI insight 20221122 22

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 ...[more]

PMID: 36166305

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Project description:IMGT, the international ImMunoGeneTics information system http://imgt.cines.fr, was created in 1989 by the Laboratoire d'ImmunoGénétique Moléculaire (LIGM) (Université Montpellier II and CNRS) at Montpellier, France. IMGT is a high quality integrated knowledge resource specialized in immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC) of human and other vertebrates, and related proteins of the immune system (RPI) of any species which belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). IMGT consists of five databases, ten on-line tools and more than 8,000 HTML pages of Web resources. IMGT provides a common access to standardized data from genome, genetics, proteome and three-dimensional structures. The accuracy and the consistency of IMGT data are based on IMGT-ONTOLOGY, a semantic specification of terms to be used in immunogenetics and immunoinformatics. IMGT-ONTOLOGY comprises six main concepts: IDENTIFICATION, CLASSIFICATION, DESCRIPTION, NUMEROTATION, ORIENTATION and OBTENTION. Based on these concepts, the controlled vocabulary and the annotation rules necessary for the immunogenetics data identification, classification, description and numbering and for the management of IMGT knowledge are defined in the IMGT Scientific chart. IMGT is the international reference in immunogenetics and immunoinformatics for medical research (repertoire analysis of the IG antibody sites and of the TR recognition sites in autoimmune and infectious diseases, AIDS, leukemias, lymphomas, myelomas), veterinary research (IG and TR repertoires in farm and wild life species), genome diversity and genome evolution studies of the adaptive immune responses, biotechnology related to antibody engineering (single chain Fragment variable (scFv), phage displays, combinatorial libraries, chimeric, humanized and human antibodies), diagnostics (detection and follow up of residual diseases) and therapeutical approaches (grafts, immunotherapy, vaccinology). IMGT is freely available at http://imgt.cines.fr.

Dataset Information

Immunogenetics associated with severe coccidioidomycosis.

Publications

Immunogenetics associated with severe coccidioidomycosis.

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