![]() was also supported by a NIH T32 Training Grant in HIV Replication and Pathogenesis (AI1049815). were supported by an NIH T32 Training Grant (GM068411). ![]() This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the manuscript and its Supporting Information files.įunding: The work was also supported by NIH grants AI127370 and AI50698 to J.M. Received: MaAccepted: JPublished: July 14, 2022Ĭopyright: © 2022 Ciesla et al. PLoS Pathog 18(7):Įditor: Deborah Lenschow, Washington University in Saint Louis, UNITED STATES Collectively, our data indicate that cytokine-induced metabolic remodeling is an important component of TNFα’s ability to promote a less permissive cell state and raises further questions about the mechanisms through which specific cytokine-induced metabolic activities contribute to various aspects of anti-viral defense.Ĭitation: Ciesla J, Moreno I Jr, Munger J (2022) TNFα-induced metabolic reprogramming drives an intrinsic anti-viral state. Inhibition of glucose metabolism during TNFα treatment prevented the expression of a variety of known cellular anti-viral proteins. We find that these TNFα-induced metabolic changes are critical for TNFα to limit the replication of diverse viruses including Human Cytomegalovirus and two Coronaviruses, OC43 and SARS-CoV-2. Our data indicate that treatment with the anti-viral cytokine TNFα induces substantial changes to cellular metabolic activity, including activating glucose metabolism. Many of the mechanisms through which cytokines promote a less permissive cell state remain unclear. These cytokines act on neighboring cells to make them less permissive to viral infection. Viral infection often activates a host cell’s intrinsic immune response resulting in the cellular secretion of cytokines, important host-defense molecules. Collectively, our data indicate that cytokine-mediated metabolic remodeling is an essential component of the anti-viral response. Consistent with the importance of glucose-driven glycosylation, glycosyl-transferase inhibition attenuated TNFα’s ability to promote the anti-viral cell state. ![]() Glycolysis was also necessary for the TNFα-mediated accumulation of several glycosylated anti-viral proteins. Our data indicate that TNFα increases the concentration of UDP-glucose, as well as the glucose-derived labeling of UDP-glucose and UDP-N-acetyl-glucosamine in a glycolytically-dependent manner. TNFα was also found to modulate the metabolism of UDP-sugars, which are essential precursor substrates for glycosylation. Further, we show that glycolysis is broadly important for TNFα-mediated anti-viral defense, as its inhibition attenuates TNFα’s ability to limit the replication of evolutionarily divergent viruses. Our data demonstrate that TNFα activates glycolysis through the induction of hexokinase 2 (HK2), the isoform predominantly expressed in muscle. Here, we find that TNFα induces significant metabolic remodeling that is critical for its anti-viral activity. Cytokines induce an anti-viral state, yet many of the functional determinants responsible for limiting viral infection are poorly understood. ![]()
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