Metabolic interference impairs influenza A virus replication by dampening vRNA synthesis

For replication, viruses exploit the host cell metabolism for biosynthesis of viral components. Recently, we could show that inhibition of glycolysis interfered with IAV replication by impairing the regulation of the viral polymerase as a transcriptase or replicase. Here, we investigated how IAV replication and polymerase regulation is influenced by other metabolic pathways which are directly or indirectly linked to glycolysis. Therefore, we inhibited glutaminolysis, fatty acid synthesis (FAS), oxidative phosphorylation (OXPHOS), and the pentose phosphate pathway (PPP). Inhibition of these metabolic pathways led to a significant reduction of viral titers. Furthermore, the inhibition of glutaminolysis, FAS and OXPHOS unbalanced the cellular glycolysis and respiration network leading to a prolonged phase of viral transcription while replication was strongly decreased. Our data indicate that affecting the cellular glycolysis and respiration balance impairs the dynamic regulation of the viral polymerase, resulting in reduced synthesis of viral genomic RNA and viral particles.