Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Krishnan, Shuba; Nordqvist, Hampus; Ambikan, Anoop T.; Gupta, Soham; Sperk, Maike; Svensson-Akusjärvi, Sara; Mikaeloff, Flora; Benfeitas, Rui; Saccon, Elisa; Ponnan, Sivasankaran Munusamy; Rodriguez, Jimmy Esneider; Nikouyan, Negin; Odeh, Amani; Ahlén, Gustaf; Asghar, Muhammad; Sällberg, Matti; Vesterbacka, Jan; Nowak, Piotr; Végvári, Ákos; Sönnerborg, Anders; Treutiger, Carl Johan; Neogi, Ujjwal

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.