Research ArticleVIRAL IMMUNOLOGY

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

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Science Immunology  02 Oct 2020:
Vol. 5, Issue 52, eabd2876
DOI: 10.1126/sciimmunol.abd2876

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Revenge against rotavirus

Rotavirus (RV) is an enteric infection that can cause severe morbidity and contributes to childhood mortality in resource-poor countries where the existing vaccine is of moderate efficacy. A previous study showed that TLR5-driven IL-22 production and NLRC4-mediated generation of IL-18 can work together to prevent or treat RV infection. Here, Zhang et al. show that IL-22 drives intestinal epithelial cell (IEC) proliferation and migration toward villus tips resulting in extrusion of differentiated IEC, which are sites of RV replication. IL-18 induces cell death of infected IEC, and together, these mechanisms accelerate clearance of RV from the intestine. These findings suggest that these cytokines may support clearance of other enteric viral infections.

Abstract

Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other’s expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved 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 cell 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 the number 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 a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

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