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

Abstract

Activators of innate immunity may have the 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-22 (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.

TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation

“…6,21,42 Thus, a systemic exposure to flagellin would at once mobilize neutrophils to mucosal surfaces and activate production of these cells. 3 This explains our previous observation that repeated treatment of mice with flagellin over a 10-day period resulted in an enormous load of neutrophils in the intestine. 3 The production phase of this process can be initiated quickly, as we observed a sixfold increase in blood neutrophils 15 hours following flagellin treatment (supplemental Figure 9).…”

“…While several populations of bone marrow-derived cells are unresponsive to flagellin, key aspects of the flagellin-induced immune response (eg, activation of the IL-23/IL-22 axis) are mediated by TLR5-expressing dendritic cells. 3,29,30 Hence, we hypothesized that flagellin-induced LSK cell proliferation might reflect its action on bone marrowderived cells. To investigate this possibility, we generated bone marrow chimeric mice in which only hematopoietic or nonhematopoietic cells expressed TLR5.…”

“…The magnitude of this increase suggested that it did not only reflect neutrophil recruitment to the intestine but involved increased neutrophil production. 3 Furthermore, bone marrow cells isolated from flagellin-treated mice had a greater capacity than untreated bone marrow to rescue lethally irradiated mice that had not been exposed to flagellin. 1 This suggests that flagellin treatment had impacted hematopoietic precursors in bone marrow.…”

“…However, multiple lines of evidence indicate that flagellin treatment has potent effects on immune cell proliferation and/or mobilization. 3,5,6 Specifically, treatment with flagellin results in a very large increase in neutrophils in the intestine. The magnitude of this increase suggested that it did not only reflect neutrophil recruitment to the intestine but involved increased neutrophil production.…”

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…The protective effects of IFN-λ in acute rotavirus infection in mice are enhanced by IL-22, which also cured chronic murine rotavirus infection (54,61). In the HIE model, pretreatment with IL-22 decreased HRV replication by 54% (Fig.…”