TBK1 and IRF3 are potential therapeutic targets in Enterovirus A71-associated diseases

Author summary EV-A71 is an important causative agent of HFMD. There is currently no specific antiviral agent to treat HFMD and the related severe complications. The underlying molecular mechanism controlling host innate immunity after EV-A71 infection is still not fully understood, especially the roles of TBK1 and IRF3. Here, we applied TBK1 inhibitor (TBK1/IKKε-IN-2) and IRF3 agonist (KIN1148) to evaluate the antiviral activities of TBK1 and IRF3 in vivo. We found through regulating EV-A71-induced type I IFN response, IRF3 agonist effectively alleviated EV-A71-induced illness, while TBK1 inhibitor aggravated disease progression. More severe pathological alterations of neuronal degeneration, muscle fiber breaks, fractured or fused alveolar walls and diffuse congestion occurred in EVA-71-infected mice with TBK1 inhibitor treatment, while no obvious pathological change occurred in EVA-71-infected mice with IRF3 agonist treatment and control mice. Furthermore, TBK1 inhibitor promoted EV-A71-induced inflammatory response, while IRF3 agonist alleviated it. Our findings suggest that TBK1 and IRF3 are potential therapeutic targets in EV-A71-induced illness for the development of new antiviral agents and therapeutic strategies.