Coxsackievirus-A10 induced RIPK3-driven necroptosis to promote the formation of inflammatory response and enhance virus production via being recognized by TLR3.

Abstract

Neuronal death and neuroinflammation has been considered as the main contributors to the progression and deterioration of HFMD caused by CV-A10. Necroptosis is a lytic and inflammatory form of cell death that plays a crucial role in viral pathogenicity. Herein, our study showed that CV-A10-infected SH-SY5Y cells induced necroptosis via activating RIPK3-depedent pathway, but not requiring RIPK1, and meanwhile triggered the release of inflammatory cytokines. Moreover, RIPK3-mediated necroptosis was also involved in virus production, which did not require RIPK1 either. Finally, it was further verified that TLR3 drove RIPK3-mediated cell death by sensing CV-A10 RNA and activating RIPK3. Collectively, our study demonstrated that initiation of necroptosis in SH-SY5Y cells induced by CV-A10 accelerated the formation of inflammatory response and promoted virus replication through triggering a TLR3-initiated RIPK3-dependent pathway of necroptosis, which advanced the current understanding of necroptosis for the neuropathogenesis of CV-A10 infection.