The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections

Abstract

Host cell metabolism is essential for the viral replication cycle and, therefore, for productive infection. Energy (ATP) is required for the receptor-mediated attachment of viral particles to susceptible cells and for their entry into the cytoplasm. Host cells must synthesize an array of biomolecules and engage in intracellular trafficking processes to enable viruses to complete their replication cycle. The tricarboxylic acid (TCA) cycle has a key role in ATP production as well as in the synthesis of the biomolecules needed for viral replication. The final assembly and budding process of enveloped viruses, for instance, require lipids, and the TCA cycle provides the precursor (citrate) for fatty acid synthesis (FAS). Viral infections may induce host inflammation and TCA cycle metabolic intermediates participate in this process, notably citrate and succinate. On the other hand, viral infections may promote the synthesis of itaconate from TCA cis-aconitate. Itaconate harbors anti-inflammatory, anti-oxidant, and anti-microbial properties. Fumarate is another TCA cycle intermediate with immunoregulatory properties, and its derivatives such as dimethyl fumarate (DMF) are therapeutic candidates for the contention of virus-induced hyper-inflammation and oxidative stress. The TCA cycle is at the core of viral infection and replication as well as viral pathogenesis and anti-viral immunity. This review highlights the role of the TCA cycle in viral infections and explores recent advances in the fast-moving field of virometabolism.

1H qNMR-Based Metabolomics Discrimination of Covid-19 Severity

“…An example is the glucose and lipid metabolism, which is known to be shifted during a high production of cytokines TNF-α, IL-6, and IL-1β and during the entry, replication, and egress of the virus at/from the host cell. 42 , 44 − 46 In detail, glucose resistance is highlighted during the production of cytokines, while lipolysis and triglyceride synthesis are upregulated. Similarly, it is also known that viruses might alter the host cell metabolism on behalf of its replication, similar to the Walburg effect, widely studied in cancer models, also known as aerobic glycolysis.…”

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis

“…Rewiring of the TCA cycle and changes in mitochondrial function are parts of metabolic reprogramming in infected cells and used in response to ROS to fuel fatty acid synthesis or deregulate cellular acetylation [ 150 ]. Increased citrate efflux out of the mitochondria is important to the TCA cycle rewiring.…”

The Interferon Response Dampens the Usutu Virus Infection-Associated Increase in Glycolysis

“…In this regard the viral impact on cellular metabolism could be a promising target with growing importance for the study of new therapeutic intervention options against virus infections (Sumbria et al, 2021). A number of viruses, namely, members of the family Flaviviridae cause metabolic alterations to support their productive infection cycle (Sanchez-Garcia et al, 2021;Sumbria et al, 2021). Thus, we explored the USUV infection-associated alterations in the bioenergetic profile in various cell lines.…”