Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection.
Sanjeev GurshaneyAnamaria Morales-AlvarezKevin EzhakunnelAndrew ManaloThien-Huong HuynhJun-Ichi AbeNhat-Tu LeDaniela WeiskopfAlessandro SetteDaniel S LupuStephen J GardellHung D NguyenPublished in: Communications biology (2023)
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.
Keyphrases
- single cell
- sars cov
- respiratory syndrome coronavirus
- flow cytometry
- rna seq
- cell proliferation
- coronavirus disease
- fatty acid
- oxidative stress
- working memory
- cell cycle
- dendritic cells
- metabolic syndrome
- high throughput
- hydrogen peroxide
- immune response
- pi k akt
- mass spectrometry
- regulatory t cells
- big data
- smoking cessation
- blood glucose
- signaling pathway
- adipose tissue
- machine learning
- type diabetes
- electronic health record
- early onset
- insulin resistance
- data analysis
- virtual reality
- weight loss
- combination therapy
- risk assessment