Picornavirus-initiated inflamation: novel parallels from Drosophila

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DESCRIPTION (provided by applicant): Virus infections are recognized as a major cause of myocarditis (or inflammation of the heart muscle), and chronic myocarditis often leads to more severe cardiac disease (including dilated cardiomyopathy) that accounts for approximately half of all heart transplant cases. In particular, picornaviruses such as type B coxsackieviruses are considered the prototypic causative agents of viral myocarditis. While the link between picornavirus infections and viral myocarditis has been well-established, little is known about the molecular mechanisms by which a picornavirus infection of the cardiomyocyte initiates inflammation. Cardiomyocytes detect the presence of a picornavirus in the cytoplasm via RNA helicases called RLRs (RIG-I-like receptors). The primary objective of this proposal is to determine how RLRs activate NF-?B to trigger inflammatory responses following picornavirus infection. Identifying the mechanisms by which the NF-?B-regulated pro-inflammatory signal is generated will inform rational therapeutic strategies to alter the balance between a beneficial antiviral response and a deleterious myocardial inflammatory reaction. We propose that picronaviruses activate RLRs to trigger formation of a novel cytoplasmic signaling complex that we call the FADDosome. Our previous work has shown that the FADDosome (comprising the molecules FADD, TRADD, RIP1 and select caspases) specifically activates NF-?B following virus infection, but the mechanism by which the FADDosome regulates NF-?B is unknown. FADD-based NF-?B activation appears to be unique in vertebrate biology, but shares strong parallels with an under-appreciated innate immune pathway in Drosophila called Immune Deficient (IMD). Based on these provocative similarities, we hypothesize that a Drosophila IMD-like signaling module is conserved in vertebrates where it mediates NF-?B activation by the FADDosome in response to RLRs. In this proposal, we will (1) draw comparisons from the established IMD pathway to identify how the FADDosome activates NF-?B following stimulation of RLRs by picornaviruses, and (2) test the feasibility of RLR-NF-?B inhibition as a therapeutic avenue for picornavirus-driven myocarditis.