TY - JOUR
T1 - WY14643 Increases Herpesvirus Replication and Inhibits IFNb Production Independently of PPARa Expression
AU - Tao, Lili
AU - Dryden, Phillip
AU - Lowe, Alexandria
AU - Wang, Guoxun
AU - Achuthkumar, Amritha
AU - Chang, Tyron
AU - Reese, Tiffany A.
N1 - Funding Information:
We thank members of the Reese labs for technical assistance, David Mangelsdorf and Steven Kleiwer for reagents and expertise, and Wenhan Zhu for help with data analysis. We also thank the UTSW Flow Cytometry core. The Reese lab is supported by the NIH (1R01AI130020-01A1 and 5U19AI142784), CPRIT (RP200118), the Pew Scholars Program.
Publisher Copyright:
Copyright © 2023 Tao et al.
PY - 2023/3
Y1 - 2023/3
N2 - 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 PPARa 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 in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARa. We found that WY14643 suppressed production of type I interferon after MHV68 infection in vitro and in vivo. Taken together, our data indicate that caution should be employed when using PPARa agonists in immuno-metabolic studies, as they can have off-target effects on viral replication through the inhibition of type I interferon production. IMPORTANCE 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 PPARa agonists in altering virus replication. Second, it shows that PPARa agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARa agonists as a research tool.
AB - 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 PPARa 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 in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARa. We found that WY14643 suppressed production of type I interferon after MHV68 infection in vitro and in vivo. Taken together, our data indicate that caution should be employed when using PPARa agonists in immuno-metabolic studies, as they can have off-target effects on viral replication through the inhibition of type I interferon production. IMPORTANCE 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 PPARa agonists in altering virus replication. Second, it shows that PPARa agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARa agonists as a research tool.
KW - MHV68
KW - PPAR
KW - PPAR agonist
KW - herpesvirus
KW - type I interferon
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U2 - 10.1128/spectrum.02337-22
DO - 10.1128/spectrum.02337-22
M3 - Article
C2 - 36715509
AN - SCOPUS:85153847279
SN - 2165-0497
VL - 11
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 2
ER -