Shu Zhu1*, Siyuan Ding2,3*, Penghua Wang4, Zheng Wei1, Wen Pan5, noah W. Palm1, Yi Yang1, Hua Yu1, Hua-Bing Li1, Geng Wang1, Xuqiu Lei1, Marcel R. de Zoete1, Jun Zhao1,6, Yunjiang Zheng1, Haiwei Chen1, Yujiao Zhao4, Kellie A. Jurado7, ningguo Feng2, Liang Shan1, Yuval Kluger6, Jun Lu5, Clara Abraham7, erol Fikrig7,8, Harry B. Greenberg2,3 & Richard A. Flavell1,8
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 signalling2–5, 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.