Abstract
Coxsackievirus B (CVB) is a common human enterovirus that can cause an array of systemic inflammatory diseases. We and others have demonstrated that macroautophagy/autophagy is activated during CVB infection leading to viral engulfment within autophagosomes. Interestingly, rather than this mechanism leading to bulk degradation of intracellular virus (also referred to as xenophagy), autophagosome-lysosomal fusion appears to be circumvented, leading to extracellular release of CVB via ejected autophagosomes. In our present study, we have found that TBK1 (TANK binding kinase 1) plays a role in limiting CVB infection by promoting autophagic flux to limit autophagy-based viral egress. This aspect of viral defense also appears to be independent of TBK1's well-characterized involvement in interferon signaling. Indeed, genetic inhibition of TBK1 significantly enhances CVB infection in vitro and dramatically increases the amount of vesicle-bound virus being released from the cell. Furthermore, inhibition of TBK1 via amlexanox treatment markedly increases serum levels of infectious extracellular vesicles (EV) and severity of pancreatitis in CVB-infected mice. In all, the identification of TBK1's involvement in the suppression of CVB egress pegs it as a promising therapeutic target for the development of novel antiviral strategies against not only CVB but potentially other viruses that exploit autophagy to promote viral spread.