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.

Keywords: host cell metabolism; metabolic reprogramming; mitochondria; tricarboxylic acid cycle; viruses.

Figure 1

Tricarboxylic acid (TCA) cycle. The TCA cycle takes place within the mitochondria and it is the source of precursors for the synthesis of biomolecules required for viral replication as well as of metabolites with signalling properties which may influence the outcome of viral infections.

Figure 2

Tricarboxylic acid (TCA) cycle-derived metabolites and their role in viral infections. The TCA cyce intermediate metabolites citrate, succinate and fumarate play key roles in vral replication and in the virus-induced inflammation process. In addition, itaconate, which is synthesized from the TCA cis-aconitate, is also endowed with anti-inflammatory and anti-viral properties.