BACKGROUND: Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. METHODS: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV). The importance of FXR in inducing IFN-I and monocytes proliferation were investigated and viral titers and T cell exhaustion were analyzed at different time points. RESULTS: This study shows that controlled levels of BAs activate FXR in hepatocytes and FXR in response upregulates the production of type I interferon. In turn, FXR maintains BAs within a balanced range to inhibit their toxic effects. The absence of FXR results in high levels of BAs, which inhibit the proliferation of monocytes and result in a defect in viral elimination, consequently leading to T cell exhaustion. CONCLUSION: We found that FXR contributes to IFN-I production in hepatocytes and balances BA levels to inhibit their toxic effects on monocytes.
BACKGROUND:Bile acids (BAs) are steroid molecules that are synthesized in the liver. In addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. The role of BAs and their receptor farnesoid X receptor (FXR) during viral infection has not been studied in detail. METHODS: By using FXR-deficient mice, we investigated the role of bile acid receptor FXR during infection with lymphocytic choriomeningitis virus (LCMV). The importance of FXR in inducing IFN-I and monocytes proliferation were investigated and viral titers and T cell exhaustion were analyzed at different time points. RESULTS: This study shows that controlled levels of BAs activate FXR in hepatocytes and FXR in response upregulates the production of type I interferon. In turn, FXR maintains BAs within a balanced range to inhibit their toxic effects. The absence of FXR results in high levels of BAs, which inhibit the proliferation of monocytes and result in a defect in viral elimination, consequently leading to T cell exhaustion. CONCLUSION: We found that FXR contributes to IFN-I production in hepatocytes and balances BA levels to inhibit their toxic effects on monocytes.
Authors: Emma S Winkler; Swathi Shrihari; Barry L Hykes; Scott A Handley; Prabhakar S Andhey; Yan-Jang S Huang; Amanda Swain; Lindsay Droit; Kranthi K Chebrolu; Matthias Mack; Dana L Vanlandingham; Larissa B Thackray; Marina Cella; Marco Colonna; Maxim N Artyomov; Thaddeus S Stappenbeck; Michael S Diamond Journal: Cell Date: 2020-07-14 Impact factor: 41.582
Authors: Ta-Chiang Liu; Justin T Kern; Umang Jain; Naomi M Sonnek; Shanshan Xiong; Katherine F Simpson; Kelli L VanDussen; Emma S Winkler; Talin Haritunians; Atika Malique; Qiuhe Lu; Yo Sasaki; Chad Storer; Michael S Diamond; Richard D Head; Dermot P B McGovern; Thaddeus S Stappenbeck Journal: Cell Host Microbe Date: 2021-05-18 Impact factor: 31.316