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

BACKGROUND: Enterovirus A71 (EV-A71) is an important causative agent of hand-foot-and-mouth disease (HFMD) associated with enormous healthcare and socioeconomic burden. Although a range of studies about EV-A71 pathogenesis have been well described, the underlying molecular mechanism in terms of innate immune response is still not fully understood, especially the roles of TANK-binding kinase 1 (TBK1) and interferon-regulatory factor 3 (IRF3). METHODOLOGY/PRINCIPAL FINDINGS: Here, we applied TBK1 inhibitor and IRF3 agonist, for the first time, to evaluate the antiviral activities of TBK1 and IRF3 in vivo. We found that, through regulating EV-A71-induced type I interferon (IFN) response, IRF3 agonist effectively alleviated EV-A71-induced illness, while TBK1 inhibitor aggravated disease progression. In addition, EV-A71 replication was suppressed in EVA-71-infected mice administrated with IRF3 agonist. On the other hand, more severe pathological alterations of neuronal degeneration, muscle fiber breaks, fractured or fused alveolar walls, and diffuse congestion occurred in EVA-71-infected mice treated with TBK1 inhibitor administration. Furthermore, we determined the concentrations of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), IL-1β, monocyte chemotactic protein-1 (MCP-1), and IL-10 in both lungs and brains of mice and found that TBK1 inhibitor promoted EV-A71-induced inflammatory response, while IRF3 agonist alleviated it, which was consistent with clinical manifestations and pathological alterations. CONCLUSIONS: Collectively, our findings suggest that TBK1 and IRF3 are potential therapeutic targets in EV-A71-induced illness.