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

Area of Science:

• Immunology
• Cellular Metabolism
• Virology

Background:

• Cellular metabolic dysregulation is a key factor in SARS-CoV-2 infection severity.
• The impact of metabolic changes on immune function during COVID-19 is not fully understood.

Purpose of the Study:

• To investigate how SARS-CoV-2 infection perturbs cellular metabolism in immune cells.
• To explore the link between immunometabolic changes and immune cell function and differentiation.
• To evaluate the therapeutic potential of targeting cellular metabolism in COVID-19.

Main Methods:

• High-dimensional flow cytometry
• Single-cell metabolomics
• Re-analysis of single-cell transcriptomic data
• Pharmacological inhibition of mitophagy with mdivi-1

Main Results:

• SARS-CoV-2 infection induces a hypoxia-linked metabolic switch towards glucose metabolism in CD8+ T cells, NKT cells, and epithelial cells.
• Metabolic dysregulation correlates with increased cellular exhaustion, reduced effector function, and impaired memory differentiation.
• Inhibition of mitophagy enhances SARS-CoV-2-specific CD8+ T cell generation, cytokine secretion, and memory cell proliferation.

Conclusions:

• SARS-CoV-2 infection significantly alters host immune cell metabolism, impacting their function and differentiation.
• Targeting immunometabolism, specifically mitophagy, presents a promising therapeutic avenue for improving immune responses in COVID-19.