Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses.

Abstract

The metabolite-sensing G protein-coupled receptors (GPCRs) bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. However, the roles of metabolite-sensing GPCRs in viral infection are not well characterized. Here, we identified metabolite-sensing GPCR TGR5 as an interferon (IFN)-stimulated gene (ISG) which had increased expression following viral infection or IFN-β stimulation in a STAT1-dependent manner. Most importantly, overexpression of TGR5 or treatment with the modified bile acid INT-777 broadly protected host cells from vesicular stomatitis virus (VSV), newcastle disease virus (NDV) and herpes simplex virus type 1 (HSV-1) infection. Furthermore, VSV and HSV-1 replication was increased significantly in Tgr5-deficient macrophages and the VSV distribution in liver, spleen and lungs was increased in Tgr5-deficient mice during VSV infection. Accordingly, Tgr5-deficient mice were much more susceptible to VSV infection than wild-type mice. Mechanistically, TGR5 facilitates type I interferon (IFN-I) production through the AKT/IRF3-signaling pathway, which is crucial in promoting antiviral innate immunity. Taken together, our data reveal a positive feedback loop regulating IRF3 signaling and suggest a potential therapeutic role for metabolite-sensing GPCRs in controlling viral diseases.

• Authors: Qingqing Xiong, Hongjun Huang, Ning Wang, Ruoyu Chen, Naiyang Chen, Honghui Han, Qin Wang, Stefan Siwko, Mingyao Liu, Min Qian, Bing Du
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 2289 ( 2018) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 30333836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gpbar1 protein, mouse
• Interferon Regulatory Factor-3
• Interferon Type I
• Irf3 protein, mouse
• Receptors, G-Protein-Coupled
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Line
• Disease Models, Animal
• Energy Metabolism
• Gene Expression
• Host-Pathogen Interactions (genetics, immunology)
• Humans
• Immunity, Innate
• Interferon Regulatory Factor-3 (metabolism)
• Interferon Type I (metabolism)
• Mice
• Mice, Knockout
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction
• Virus Diseases (etiology, metabolism, mortality, pathology)
• Virus Replication (immunology)