Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

Abstract

SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD + , coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3 + Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.

Duration of SARS-CoV-2 RNA positivity from various specimens and clinical characteristics in patients with COVID-19: a systematic review and meta-analysis

“…Ct values of RT-PCR in the patients with comorbidities were lower [ 86 ]. Hypertension, cardiovascular diseases, diabetes, and obesity related to abnormal immune response [ 117 ]. The outcomes of COVID-19 are primarily influenced by comorbidities and particular disease states or treatments in patients with rheumatic diseases [ 118 ].…”

Plasma Metabolomic Alterations Induced by COVID-19 Vaccination Reveal Putative Biomarkers Reflecting the Immune Response

“…Inclusion of glutamine as an adjuvant in the treatment of COVID-19 patients showed a putative synergistic effect on immune defense [ 37 ]. Glutamine deficiency and increased hyaluran in the lungs have emerged as central metabolic characteristics that prompt COVID-19 patients to severe pathophysiology [ 38 ]. Metabolomic studies have also shown a reduced glutamine/glutamate ratio in COVID-19 patients, indicating a metabolic rewiring of energy metabolism and systematic implications during infection that could be clinically valuable [ 17 , 39 ].…”

Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic

“…Glutamine is also one of the three amino acids needed for glutathione (GSH) synthesis. GSH, a tripeptide formed by glutamate, glycine and cysteine, represents the most important body endogenous antioxidant system, being active mainly in the cell mitochondria and nucleus (102,103). Intracellular glutamine as glutamate precursor is fundamental for the synthesis of GSH (99).…”