Interplay between Cellular Metabolism and Cytokine Responses during Viral Infection

Abstract

Metabolism and immune responses are two fundamental biological processes that serve to protect hosts from viral infection. As obligate intracellular pathogens, viruses have evolved diverse strategies to activate metabolism, while inactivating immune responses to achieve maximal reproduction or persistence within their hosts. The two-way virus-host interaction with metabolism and immune responses choreograph cytokine production via reprogramming metabolism of infected cells/hosts. In return, cytokines can affect the metabolism of virus-infected and bystander cells to impede viral replication processes. This review aims to summarize our current understanding of the cross-talk between metabolic reprogramming and cytokine responses, and to highlight future potential research topics. Although the focus is placed on viral pathogens, relevant findings from other microbes are integrated to provide an overall picture, particularly when corresponding information on viral infection is lacking.

Keywords: cytokine response; immunometabolism; innate immunity; metabolic reprogramming.

Figure 1

Schematic illustration of interplay between host metabolism and cytokine induction. Upon infection, pattern recognition receptors (such as Toll-like receptors (TLRs), retinoic-acid-inducible protein I (RIG-I)-like receptors (RLRs) and cytosolic sensors (cGAS)) sense pathogen-associated molecular pattern and dimerize with their cognate adaptor molecules to activate IKKαβ and TBK-1/IKKε. These kinases in turn activate IRF3 and NF-κB, thereby promoting cytokine production. Central metabolic pathways, including the glycolysis, tricarboxylic acid (TCA) cycle and lipid metabolism, are crucial for cell proliferation and viral replication. The immune-modulating effect of metabolism can stem from metabolites, metabolic enzymes and organelles. Conversely, the metabolism-programming activity of cytokine response can originate from immune signaling components or cytokine signaling thereof. Mitochondria serve as an excellent example that integrates diverse players at the interface of immune response and metabolism. Metabolites, such as succinate and citrate, directly or indirectly regulate NF-κB activation. Metabolic enzymes (e.g., mammalian target of rapamycin (mTOR) and adenosine 5′-monophosphate–activated protein kinase (AMPK)) play regulatory roles in both metabolism and immune responses. Metabolic organelles, such as mitochondria and lysosomes, deploy multiple strategies to interfere with pathogen replication and reprogram metabolic activity for intrinsic immune defense, via modulating mitochondrial fission and fusion (e.g., Mfn2) and activating the autophagy-lysosome degradative pathway. Blue arrows represent cellular metabolic processes and orange arrows indicate innate immune signaling pathways.