NLRC5 Regulates Enterovirus 71 Infection Through an IFN-β-Dependent Pathway

During viral Infection, NLR family CARD domain-containing protein 5 (NLRC5) participates in innate immunity through multiple mechanisms. These include regulating type I interferon and related immune factor expression, as well as modulating immune cell functions, such as cytotoxic T lymphocytes (CTLs) and macrophages, thereby promoting Antiviral defence and maintaining immune homeostasis. Our study demonstrates that (1) Enterovirus 71 (EV71) Infection upregulates NLRC5 expression through the RIG-I-IRF3-mediated IFN-β pathway, which in turn promotes MHC-I molecule expression and (2) NLRC5 suppresses EV71 replication and simultaneously restrains excessive inflammatory responses by fine-tuning IFN-β production through a negative feedback loop. This loop operates via two distinct mechanisms, namely, direct downregulation of key IFN-β pathway mediators (e.g., RIG-I and IRF3) and binding to the 5'UTR of the EV71 genome to inhibit viral replication, thereby indirectly dampening the IFN-β signal. Furthermore, we show that EV71 activates the NLRC5-dependent MHC-I response in an IFN-β-dependent manner. Collectively, these results elucidate the dual role of NLRC5 during EV71 Infection, offering novel insights into viral pathogenesis and highlighting potential targets for Antiviral drug development.

EV71; IFN-β; MHC-I; NLRC5; homeostasis; innate immunity.