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Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis

  1. Author:
    Drummond, Rebecca A
    Desai, Jigar V
    Hsu, Amy P
    Oikonomou, Vasileios
    Vinh, Donald C
    Acklin, Joshua A
    Abers, Michael S
    Walkiewicz, Magdalena A
    Anzick, Sarah L
    Swamydas, Muthulekha
    Vautier, Simon
    Natarajan, Mukil
    Oler, Andrew J
    Yamanaka, Daisuke
    Mayer-Barber, Katrin D
    Iwakura, Yoichiro
    Bianchi, David
    Driscoll, Brian
    Hauck, Ken
    Kline, Ahnika
    Viall, Nicholas Sp
    Zerbe, Christa S
    Ferré, Elise Mn
    Schmitt, Monica M
    DiMaggio, Tom
    Pittaluga, Stefania
    Butman, John A
    Zelazny, Adrian M
    Shea, Yvonne R
    Arias, Cesar A
    Ashbaugh, Cameron
    Mahmood, Maryam
    Temesgen, Zelalem
    Theofiles, Alexander G
    Nigo, Masayuki
    Moudgal, Varsha
    Bloch, Karen C
    Kelly, Sean G
    Whitworth, M Suzanne
    Rao, Ganesh
    Whitener, Cindy J
    Mafi, Neema
    Gea-Banacloche, Juan
    Kenyon, Lawrence C
    Miller, William R
    Boggian, Katia
    Gilbert, Andrea
    Sincock, Matthew
    Freeman, Alexandra F
    Bennett, John E
    Hasbun, Rodrigo
    Mikelis, Constantinos M
    Kwon-Chung, Kyung J
    Belkaid, Yasmine
    Brown, Gordon D
    Lim, Jean K
    Kuhns,Doug
    Holland, Steven M
    Lionakis, Michail S

  2. Author Address

    Fungal Pathogenesis Section and., Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA., Division of Infectious Diseases, McGill University Health Centre (MUHC), and Infectious Disease Susceptibility Program, Research Institute-MUHC, Montreal, Quebec, Canada., Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Division of Intramural Research, NIAID, NIH, Bethesda, Maryland, USA., Research Technologies Branches, NIAID, NIH, Hamilton, Montana, USA., Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, Maryland, USA., Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan., Inflammation and Innate Immunity Unit, LCIM, NIAID, NIH, Bethesda, Maryland, USA., Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan., National Institute of Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland, USA., Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), Bethesda, Maryland, USA., Radiology and Imaging Sciences and., Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA., Division of Infectious Diseases, Houston Methodist Hospital, Houston, Texas, USA., Center for Infectious Research, Houston Methodist Research Institute, Houston, Texas, USA., Division of Infectious Diseases, UCSF, San Francisco, California, USA., Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA., Division of Hospital Medicine, Mayo Clinic, Rochester, Minnesota, USA., Division of Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Department of Internal Medicine, St. Joseph Mercy Hospital, Ann Arbor, Michigan, USA., Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Cook Children 39;s Health Care System, Fort Worth, Texas, USA., Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA., Division of Infectious Diseases, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA., Division of Infectious Diseases, Mayo Clinic Hospital, Phoenix, Arizona, USA., Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, Switzerland., Department of Pathology, University of Texas Health San Antonio, San Antonio, Texas, USA., Wilmington Health, Wilmington, North Carolina, USA., Department of Internal Medicine, University of Texas Health Science Center, Houston, Texas, USA., Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA., Department of Pharmacy, University of Patras, Patras, Greece., Molecular Microbiology Section, LCIM and., Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, NIAID, NIH, Bethesda, Maryland, USA., Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom., Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,
    1. Year: 2022
    2. Date: Nov 15
    3. Epub Date: 2022 11 15
  2. Journal: The Journal of Clinical Investigation
    1. 132
    2. 22
  4. Type of Article: Article
  5. Article Number: e159348
  1. Abstract:

    Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient 39;s PBMCs failed to produce TNF-a and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-a production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-a- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

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  2. DOI: 10.1172/JCI159348
  3. PMID: 36377664
  4. PMCID: PMC9663159
  5. PII : 159348

Library Notes

  1. Fiscal Year: FY2022-2023
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