Tao Lili, Dryden Phillip, Lowe Alexandria, Wang Guoxun, Achuthkumar Amritha, Chang Tyron, Reese Tiffany A
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Microbiol Spectr. 2023 Jan 30;11(2):e0233722. doi: 10.1128/spectrum.02337-22.
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 gammaherpesvirus infection using murine gammaherpesvirus-68 (MHV68, MuHV-4). We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication . , WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. We found that WY14643 suppressed production of type I interferon after MHV68 infection and . 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 through the inhibition of type I interferon production. PPAR 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 for two reasons. First, it shows a role for PPARα agonists in altering virus replication. Second, it shows that PPARα agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.
过氧化物酶体增殖物激活受体（PPAR）激动剂常用于治疗人类的代谢紊乱，因为它们可调节脂肪酸氧化和胆固醇代谢。除了在控制代谢方面的作用外，PPAR激动剂还可调节炎症，并且在自身免疫模型中具有免疫抑制作用。我们旨在测试使用临床相关配体激活PPARα是否会影响鼠γ疱疹病毒68（MHV68，鼠疱疹病毒4型）感染。我们发现PPAR激动剂WY14643和非诺贝特可增加疱疹病毒复制。此外，WY14643可增加病毒复制并导致小鼠死亡。出乎意料的是，这些作用被证明与PPARα无关。我们发现WY14643在MHV68感染后可抑制I型干扰素的产生。综上所述，我们的数据表明，在免疫代谢研究中使用PPARα激动剂时应谨慎，因为它们可通过抑制I型干扰素的产生对病毒复制产生脱靶效应。PPAR激动剂在临床上用于治疗代谢和炎症性疾病。由于已知病毒会将宿主代谢重编程以使其自身受益，因此免疫、代谢和病毒学的交叉领域是一个重要的研究领域。我们的文章在该领域做出了重要贡献，原因有两个。首先，它显示了PPARα激动剂在改变病毒复制方面的作用。其次，它表明PPARα激动剂可以以与其预测靶点无关的方式影响病毒复制。这一知识对于任何寻求将PPARα激动剂用作研究工具的人都很有价值。
