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

## TL;DR

This study shows how NLRC5 helps control Enterovirus 71 infection by regulating immune responses and limiting viral replication.

## Contribution

The study reveals a dual role of NLRC5 in suppressing EV71 replication and modulating immune responses via an IFN-β-dependent pathway.

## Key findings

- EV71 infection increases NLRC5 expression through the RIG-I-IRF3-mediated IFN-β pathway, promoting MHC-I molecule expression.
- NLRC5 suppresses EV71 replication and limits inflammation by downregulating IFN-β pathway mediators and binding to the viral genome.
- EV71 activates the NLRC5-dependent MHC-I response in an IFN-β-dependent manner.

## Abstract

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.