Post-COVID impairment of T cell responses to community-acquired pathogens can be modified by activating cellular metabolism.

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic, though underlying causes remain elusive. Potential causes ranging from increased hospitalizations during the pandemic or greater use of antibiotics have been proposed, but precisely why rates remain high today is unknown. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell responses. Using donor-matched peripheral blood samples from 31 COVID-naïve individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV)-stimulated T cell responses were impacted by SARS-CoV-2 infection. Post-COVID CD4 memory T cells exhibited decreased activation- and increased mitochondrial redox-related gene expression. Despite this, mitochondrial flux and reactive oxygen species production were functionally limited in post-COVID antigen-specific T cells after stimulation with IAV, SA, and VZV. Post-COVID plasma was depleted in carnitine and TCA cycle species important for activating fatty acid oxidation, and this correlated with a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways. Metabolic perturbations ultimately resulted in diminished use of catabolic, energy-generating pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Activating mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may inhibit T cell metabolism upon exposure to commonly encountered pathogens, which can be partly corrected with common medications that activate mitochondrial metabolism. Our findings may have significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.