Cardiac viral infection is a common cause of heart failure for which therapeutics are lacking. Viruses primarily damage the heart by directly lysing host cells and causing widespread necrosis. The heart responds to infection by recruiting inflammatory cells to fight and prevent the spread of the virus. Inflammation is essential for a successful antiviral response, but excessive inflammation can cause a net harm to the myocardium during infection. The heart must carefully tune inflammation to prevent viral proliferation while avoiding the harm caused by excessive inflammation. Understanding the factors involved in tuning the heart's inflammatory response will be necessary to develop therapeutics for cardiac viral infection. We discovered that a protein called BEX1 (brain expressed X-linked 1) serves a pro-inflammatory role in the heart during sterile injury. We have also found that BEX1 acts in cardiomyocytes as part of a ribonucleoprotein complex regulating the level of pro-inflammatory mRNAs. Nevertheless, the direct mechanism by which BEX1 regulates cardiac inflammation has not been elucidated, and it is not known if BEX1 regulates the heart's response to virus infections. In this proposal we seek to understand BEX1's role in the response of the heart to viruses with the following aims: 1) To determine the effect of BEX1 on cardiotropic viral infection in vivo; 2) To determine the contribution of BEX1 to antiviral gene programs in the heart; and 3) To elucidate the mechanism by which BEX1 regulates antiviral responses. Preliminary data have led us to the hypothesis that BEX1 plays an antiviral role by regulating a protein called EPRS (glutamyl-prolyl-tRNA synthetase). Evaluating this hypothesis and elucidating the role of BEX1 in immunity and inflammation will be necessary to gain a better understanding of viral infection and inflammatory diseases, and could lead to the discovery of valuable therapeutic targets.
This project aims to understand how the heart protects itself from viruses. Viral infection is a common cause of heart failure. Understanding how the heart responds to viruses will give us the information needed to develop new medications to cure or prevent virus- induced heart failure.
