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bioRxiv · 10.1101/774984

IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection

Zhang, Z. A.·Zou, J.·Shi, Z.·Zhang, B.·Etienne-Mesmin, L.·Chassaing, B.·Gewirtz, A.
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Abstract

Administration of bacterial flagellin elicits production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede this virus. Although IL-18 and IL-22 induce each others expression, we found that IL-18 and IL-22 both impeded RV independently of each other and did so by distinct mechanisms, in both cases via activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced pyroptotic death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in levels of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that IL-18/22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

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Zhang, Z. A., Zou, J., Shi, Z., Zhang, B., Etienne-Mesmin, L., Chassaing, B., Gewirtz, A.. 2019-09-18. IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection. https://doi.org/10.1101/774984

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