Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection

Sanjeev Gurshaney, Anamaria Morales-Alvarez, Kevin Ezhakunnel, Andrew Manalo, Thien Huong Huynh, Jun Ichi Abe, Nhat Tu Le, Daniela Weiskopf, Alessandro Sette, Daniel S. Lupu, Stephen J. Gardell, Hung Nguyen

Research output: Contribution to journalArticlepeer-review


Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.

Original languageEnglish (US)
Article number374
JournalCommunications Biology
Issue number1
StatePublished - Apr 7 2023


  • Humans
  • COVID-19
  • SARS-CoV-2
  • CD8-Positive T-Lymphocytes
  • COVID-19 Drug Treatment

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)


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