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

Area of Science:

• Immunology
• Virology
• Cardiology

Background:

• Viral myocarditis is a significant cause of heart disease and death.
• Type I interferon (IFN) responses are vital for protection against viral myocarditis, but their mechanisms are not fully understood.
• A Disintegrin And Metalloproteinase domain 9 (ADAM9) has been linked to inflammatory diseases, but its role in viral infections was unknown.

Purpose of the Study:

• To investigate the role of ADAM9 in the innate immune response to viral infections, specifically in the context of viral myocarditis.
• To elucidate the molecular mechanisms by which ADAM9 influences antiviral signaling pathways.

Main Methods:

• Mice lacking ADAM9 were infected with encephalomyocarditis virus (EMCV).
• Type I IFN responses and viral load were assessed in infected mice.
• The interaction between ADAM9 and melanoma differentiation-associated protein 5 (MDA5) was studied.

Main Results:

• Mice deficient in ADAM9 exhibited increased susceptibility to EMCV-induced death.
• ADAM9-deficient mice failed to mount a robust type I IFN response, particularly against positive-sense, single-stranded RNA viruses.
• ADAM9 was found to bind to MDA5, promoting its oligomerization and subsequent activation of the mitochondrial antiviral-signaling protein (MAVS) pathway.

Conclusions:

• ADAM9 plays a critical role in the innate antiviral response by facilitating MDA5-mediated type I IFN production.
• This ADAM9-dependent pathway is essential for protection against virus-induced cardiac damage and mortality.
• ADAM9 represents a potential therapeutic target for treating viral myocarditis.