Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18

Activators of innate immunity may have potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin (IL)-22, which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection, and thus holds promise as a broad-spectrum antiviral agent. Total mRNA from intestinal epithelial cells of Rag1-/- mice treated with PBS, IL-18, IL-22 or IL-22/IL-18 was assayed for RNA sequencing.