Chemokine CCL6 Plays Key Role in the Inhibitory Effect of Vitamin A on Norovirus Infection

Norovirus (NoV) is the most common viral cause of acute gastroenteritis worldwide. Vitamin A has demonstrated the potential to protect against gastrointestinal infections. However, the effects of vitamin A on human norovirus (HuNoV) infections remain poorly understood. This study aimed to investigate how vitamin A administration affects NoV replication. We demonstrated that treatment with retinol or retinoic acid (RA) inhibited NoV replication in vitro based on their effects on HuNoV replicon-bearing cells and murine norovirus-1 (MNV-1) replication in murine cells. MNV replication in vitro showed significant transcriptomic changes, which were partially reversed by retinol treatment. RNAi knockdown of CCL6, a chemokine gene that was downregulated by MNV infection but upregulated by retinol administration, resulted in increased MNV replication in vitro. This suggested a role of CCL6 in the host response to MNV infections. Similar gene expression patterns were observed in the murine intestine after oral administration of RA and/or MNV-1.CW1. CCL6 directly decreased HuNoV replication in HG23 cells, and might indirectly regulate the immune response against NoV infection. Finally, relative replication levels of MNV-1.CW1 and MNV-1.CR6 were significantly increased in CCL6 knockout RAW 264.7 cells. This study is the first to comprehensively profile transcriptomes in response to NoV infection and vitamin A treatment in vitro, and thus may provide new insights into dietary prophylaxis and NoV infections.