Journal Article

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

Rojas-Quintero, Joselyn, Baer, Christina E., McDougall, William, Kyawe, Pyae P., Cashman, Timothy, MacKay, Christopher R., Liu, GuanQun, Trivedi, Chinmay M., Bazzone, Lindsey E., Qaisar, Natasha, Finberg, Robert W., Guo, Zhiru, King, Michael, Zhu, Junji, Brass, Abraham L., Owen, Caroline A., Kurt-Jones, Evelyn A., Gack, Michaela U.

2024

Overview

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. Mice lacking A Disintegrin and Metalloproteinase 9 (ADAM9) do not mount Type 1 interferon responses against encephalomyocarditis infection. Here, Bazzone et al show that ADAM9 regulates innate immune responses via by MDA5.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
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