ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection.

Autor: Bazzone LE; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Zhu J; Florida Research and Innovation Center, Cleveland Clinic, Port St Lucie, FL, USA., King M; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Liu G; Florida Research and Innovation Center, Cleveland Clinic, Port St Lucie, FL, USA., Guo Z; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA., MacKay CR; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Kyawe PP; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Qaisar N; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Rojas-Quintero J; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Owen CA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Brass AL; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA., McDougall W; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA., Baer CE; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA, USA., Cashman T; Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Trivedi CM; Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Gack MU; Florida Research and Innovation Center, Cleveland Clinic, Port St Lucie, FL, USA., Finberg RW; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA, USA., Kurt-Jones EA; Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA. Evelyn.Kurt-Jones@umassmed.edu.; Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA, USA. Evelyn.Kurt-Jones@umassmed.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 16; Vol. 15 (1), pp. 4153. Date of Electronic Publication: 2024 May 16.
DOI: 10.1038/s41467-024-48524-6
Abstrakt: Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.
(© 2024. The Author(s).)
Databáze: MEDLINE
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