Nlrp6 regulates intestinal antiviral innate immunity

Wang, P., Zhu, S., Yang, L., Cui, S., Pan, W., Jackson, R., Zheng, Y., Rongvaux, A., Sun, Q., Yang, G., Gao, S., Lin, R., You, F., Flavell, R. and Fikrig, E.

Science 2015, 350(6262): 826-830.

Speaker: Li-Chun Wang (王立君)                                        Time: 14:00~15:00, Mar 23, 2016

Commentator: Dr. Shun-Hua Chen (陳舜華老師)       Place: Room 601

Abstract:

Innate immunity is the first line defense to protect our body against pathogen infection.  Pattern recognition receptors (PRRs) are distributed at different subcellular compartments, including the cell surface, endolysosomes, and the cytosol, to detect pathogen-associated molecular patterns (PAMPs). Upon detecting PAMPs, PRRs trigger the production of interferons and proinflammatory cytokines, and also link to intrinsic defenses. This article focuses on the nucleotide oligomerization domain (NOD)-like receptors (NLRs) which are innate immune cytosolic pathways. Previous work has shown the functional roles of several NLRs in regulating antiviral immunity.  Recent work revealed a critical role for Nlrp6 in the regulation of antibacterial immune responses. Nlrp6 has been reported to exhibit a tissue- and cell-type-specific pattern of expression, with the highest level in intestinal epithelial cells (IECs). Therefore, the authors were interested in investigating whether Nlrp6 plays a key role in the control of enteric virus infection at the intestinal interface. Results from in vivo studies showed that Nlrp6 knockout mice were highly susceptible to the infection of an encephalomyocarditis virus (EMCV) when mice were challenged by the oral route but not the intraperitoneal route. And they used co-housed mice to rule out the influence of microbiota to EMCV infection in intestine. From Co-immunoprecipitation results, they found that the Nlrp6 interacted with DEAH-box helicase 15 (Dhx15) and bound viral RNA via Dhx15. Furthermore, results from qPCR analysis confirmed that upon EMCV infection, Nlrp6 knockout mice exhibited the significantly decreased expression of type I/III interferons (IFNs) and interferon stimulate genes (ISGs) expression when infected EMCV. Taken together, Nlrp6 controls enteric virus infection in the intestine by interacting with an RNA sensor, Dhx15, to trigger MAVS inducing type I/III IFNs dependent antiviral responses. This inflammasome-independent pathway of Nlrp6 demonstrates its importance against diverse pathogen in intestine.

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