Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells

Nature. 2017 Jun 29;546(7660):667-670. doi: 10.1038/nature22967. Epub 2017 Jun 21.

Abstract

Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il)-18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspase 1 / metabolism
  • DEAD-box RNA Helicases / metabolism
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology*
  • Female
  • Immunity, Innate
  • Inflammasomes / chemistry
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Interleukin-18 / immunology
  • Intestinal Mucosa / metabolism
  • Intestines / cytology*
  • Intestines / immunology
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphate-Binding Proteins
  • Pyroptosis
  • RNA, Double-Stranded / metabolism
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism*
  • Rotavirus / growth & development
  • Rotavirus / immunology*
  • Rotavirus Infections / immunology*
  • Rotavirus Infections / virology*

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Dhx9 protein, mouse
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Intracellular Signaling Peptides and Proteins
  • NLR protein, mouse
  • Phosphate-Binding Proteins
  • Pycard protein, mouse
  • RNA, Double-Stranded
  • Receptors, G-Protein-Coupled
  • Caspase 1
  • DEAD-box RNA Helicases