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

Sci Immunol. 2020 Oct 2;5(52):eabd2876. doi: 10.1126/sciimmunol.abd2876.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • Interleukin-18
  • Interleukins
  • interleukin-22