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.
Highlights
Diet and its metabolites, as well as bacterial metabolites, are increasingly recognized for their important roles in the immune system
Our previous studies have demonstrated that P2Y6 [11], P2Y13 [12], GPR146 [13], LGR4 [14], and GPR54 [15] are all related to viral infection in distinctive manners
We found that INT-777 inhibited vesicular stomatitis virus (VSV) infection in wild-type but not in Tgr5-deficient Peritoneal macrophages (PEMs), which confirmed the specific activation of TGR5 by INT-777 (Figure 3F)
Summary
As well as bacterial metabolites, are increasingly recognized for their important roles in the immune system. More and more GPCRs including free fatty acid receptors [5], purinergic receptors [6], adenosine receptors [7], dopamine receptors [8], and R-spondins receptors [9] have been found to regulate immune responses. Not surprisingly, these receptors carry out a multitude of tasks in viral infection. Identification of additional GPCRs in viral infection and related immune responses may be clinically important in the prevention and control of viral infectious diseases
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