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

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.

• Authors: Zhan Zhang, Jun Zou, Zhenda Shi, Benyue Zhang, Lucie Etienne-Mesmin, Yanling Wang, Xuyan Shi, Feng Shao, Benoit Chassaing, Andrew T Gewirtz
• Journal: Science immunology (Sci Immunol) Vol. 5 Issue 52 (10 02 2020) ISSN: 2470-9468 [Electronic] United States
• PMID: 33008915 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Interleukin-18
• Interleukins

Topics

• Animals
• Anoikis (immunology)
• Cell Movement (immunology)
• Cell Proliferation
• Disease Models, Animal
• Epithelial Cells (immunology, pathology, virology)
• Female
• Humans
• Interleukin-18 (genetics, immunology, metabolism, therapeutic use)
• Interleukins (genetics, immunology, metabolism, therapeutic use)
• Intestinal Mucosa (cytology, immunology, pathology, virology)
• Male
• Mice
• Mice, Knockout
• Rotavirus (immunology)
• Rotavirus Infections (drug therapy, immunology, virology)
• Signal Transduction (immunology)
• Interleukin-22