Investigating the Roles of Sirtuins During CVB3 Infection and Innate Immunity

Coxsackievirus B3 (CVB3) is an enterovirus that chronically infects heart tissue, leading to dilated cardiomyopathy. However, no vaccines or antivirals exist for CVB3 infection or to treat CVB3-induced dilated cardiomyopathy, except for a heart transplant. Sirtuins (SIRTs), class III lysine deacetylases, have diverse and complex roles in cellular functions, contributing to energy production, NF-κB signaling, cell cycle regulation, and inflammation. Previous studies showed that SIRTs are essential for hepatitis B and A viral replication and regulate the IFN response during viral infection. However, the role of SIRT1 and 2 during CVB3 infection is entirely unknown. CVB3-infected SIRT1 and SIRT2 knockout cells saw a significant decrease in viral titers compared to wildtype cells, and preliminary studies indicate SIRT1 and SIRT2 protein levels are stabilized during CVB3 infection, co-localize with CVB3 replication complexes and inhibit interferon-stimulated gene promoter binding and transcription. These data lead us to hypothesize that SIRT1 and 2 play dual roles during CVB3 infection: promoting CVB3 replication directly and inhibiting the immune response.