WY14643 Increases Herpesvirus Replication Independent of PPARα Expression and Inhibits IFNβ Production
Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPARα agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. Investigating the mechanism of action for WY14643, we found that it suppresses production of type I interferon by inhibiting stimulator of interferon (STING), which lies downstream of the cytoplasmic DNA sensor cGAS. Thus, WY14643 regulates interferon downstream of cytoplasmic DNA recognition and increases herpesvirus replication in a PPARα-independent manner. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication.