Role of inflammasomes in the pathogenesis caused by human norovirus

Abstract

Human noroviruses (HuNoVs) are a common cause of foodborne illness and severe childhood diarrhea and are responsible for most acute gastroenteritis outbreaks worldwide. HuNoV specifically infects the intestinal epithelial cells, induces inflammation and cell death, and consequently resulting in villus blunting. Interleukin-18 (IL-18), a proinflammatory cytokine, is elevated in HuNoV-infected patients. IL-18 is mainly expressed in epithelial cells, and uncontrolled secretion of the IL-18 is responsible for severe gut inflammatory diseases. However, the mechanisms underlying IL-18 secretion induced by HuNoV have not been revealed. Here we revealed that the HuNoV RdRp protein promotes cleavage of pro-caspase-1 in reconstituted HEK293T and THP-1 cells. importantly, RdRp is associated in the inflammasome complex by directly binding to NLRP3 and NLRP6. In a human intestinal enteroid (HIE) model, GII.4 infection increased the expression of NLRP6 inflammasome components, including NLRP6, ASC, Caspase-1, and IL-18, indicating that HuNoV infection can induce the priming phase for inflammasome activation. Most importantly, GII.4 infection affects NLRP6-ASC complex formation and IL-18 secretion. Therefore, we propose that upon HuNoV infection, viral RdRp protein interacts with NLRP6 to facilitate inflammasome complex assembly and IL-18 maturation in human intestinal epithelium.