Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19

Abstract

Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8 + T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future. Supplementary Information The online version contains supplementary material available at 10.1007/s00430-021-00727-0.

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…The value of GSH and nutritional strategies like amino acids, vitamins, minerals, phytochemicals, sulforaphane to enhance cellular Nrf2, and other supplements used to restore GSH levels ( Minich and Brown, 2019 ; Hermel et al, 2021 ) as adjunct treatments for SARS-CoV-2 infection needs to be further emphasized. Reestablishing the cellular metabolic homeostasis in SARS-CoV-2 infection and COVID-19 disease especially in the lungs, could become paramount to balance altered innate and adaptive immunity and cell function and reduce morbimortality ( Hsu et al, 2022 ; Li S. et al, 2022 ). COVID-19 of the respiratory system appears to be a complex disease that may resist finding a single silver bullet intervention ( Brosnahan et al, 2020 ).…”

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

“…Host-dependent dysregulation of glycolysis, among other metabolic pathways, following SARS-CoV-2 infection was also evident in transcriptomic data obtained from different human respiratory cell lines and various patient samples 58 . In addition, single-nucleus RNAseq data from lung tissue of deceased COVID-19 patients found changes in genes related to several metabolic pathways, including glycolysis and OxPhos 59 . Besides, mild ischemia (early stages) is characterized by increased glycolytic flux with concomitant increased glucose uptake 48 .…”

Metabolism of NK cells during viral infections

“…In this study, high levels of some metabolic pathways (glycolysis, inositol phosphate and glycerolipid metabolism) and two enzymes in glycerolipid metabolism pathway (lipin 1 and lipin 2) were found. These metabolic changes may contribute to enhance NK cell functions, such as chemotaxis, degranulation and cytotoxicity ( 94 ).…”