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How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.

Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multi-omics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and their association with disease severity. We used multi-omics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell line models along with immune phenotyping of metabolite transporters in patient blood to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multi-omics data to regulate the viral reproduction in vitro. COVID-19 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, GLUT1, in CD8+ T-cells, intermediate and non-classical monocytes, and amino acid transporter, xCT, in classical, intermediate, and non-classical monocytes. In in vitro lung epithelial cell (Calu-3) infection model we found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that SARS-CoV-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity., Graphical abstract