Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells

The inflammasome receptor Nlrp9b defends against enteric viruses by interacting with double-stranded viral RNA-bound helicase Dhx9, triggering gasdermin-D-dependent pyroptotic cell death of infected cells and secretion of Il-18. Rotaviruses cause severe and often fatal gastroenterological illnesses in young children. The mechanism by which such enteric viruses are detected and restricted in vivo is largely unknown. Richard Flavell and colleagues report how the inflammasome receptor Nlrp9 helps to defend against enteric viruses, via RNA helicase Dhx9, by interacting with double-stranded viral RNA. This interaction triggers gasdermin-D-dependent pyroptotic cell death of infected cells and secretion of IL-18. This innate immune signalling functions uniquely in intestinal epithelial cells and could reveal useful targets in the modulation of viral defences. Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide1. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-κB signalling2,3,4,5, 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.