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 PPAR with clinically relevant ligands could impact herpesvirus infection using the model strain murine gammaherpesvirus-68. We found that PPAR 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 PPAR. 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 PPAR-independent manner. Taken together, our data indicate that caution should be employed when using PPAR agonists in immuno-metabolic studies, as they can have off-target effects on viral replication. ImportancePPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field because for two reasons. First, it shows a role for PPAR agonists in altering virus detection by cells. Second, it shows that PPAR agonists can affect virus replication in a manner unrelated to their expected genetic function. This knowledge is valuable for anyone seeking to use PPAR agonists as a research tool.