Metabolic Control of Viral Infection through PPAR-α Regulation of STING Signaling

Peroxisomal proliferator activated receptors (PPARs) are sensors of dietary lipids and pharmacological targets in the treatment of metabolic disorders. PPAR ligands are also immunosuppressive. However, their function during infection is debated and the mechanisms that underlie their immunoregulatory properties are unclear. We investigated the consequences of PPAR activation during herpesvirus infection. We found that activation of PPAR- increased herpesvirus replication, suppressed type I interferon production and induced reactive oxygen species (ROS). We discovered that ROS induced by PPAR- stimulation suppressed the cytoplasmic DNA sensing pathway after direct activation of stimulator of interferon (STING), the ER adapter downstream of cytoplasmic DNA recognition. Although high ROS induces inflammasome activation and cytokine production, we found that ROS inhibited interferon production after cytoplasmic DNA recognition. Treatment of mice with a clinically relevant agonist of PPAR- increased herpesvirus replication and pathogenesis, comparable to levels observed previously in type I interferon receptor knockout mice. These findings reveal that activation of PPAR- regulates immunity to cytoplasmic DNA and DNA virus infection through inhibition of interferon. Moreover, these results demonstrate that STING signaling and interferon production is regulated by ROS.