Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has caused the death of almost 7 million people worldwide. While vaccinations and new antiviral drugs have greatly reduced the number of COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. Accumulating clinical data have discovered a deficiency of circulating glutamine in patients with COVID-19 that associates with disease severity. Glutamine is a semi-essential amino acid that is metabolized to a plethora of metabolites that serve as central modulators of immune and endothelial cell function. A majority of glutamine is metabolized to glutamate and ammonia by the mitochondrial enzyme glutaminase (GLS). Notably, GLS activity is upregulated in COVID-19, favoring the catabolism of glutamine. This disturbance in glutamine metabolism may provoke immune and endothelial cell dysfunction that contributes to the development of severe infection, inflammation, oxidative stress, vasospasm, and coagulopathy, which leads to vascular occlusion, multi-organ failure, and death. Strategies that restore the plasma concentration of glutamine, its metabolites, and/or its downstream effectors, in conjunction with antiviral drugs, represent a promising therapeutic approach that may restore immune and endothelial cell function and prevent the development of occlusive vascular disease in patients stricken with COVID-19.

Keywords: COVID-19; ammonia; coagulopathy; glutaminase; glutamine; heme oxygenase-1; immune and endothelial dysfunction; vascular disease.

Figure 1

Summary of Gln transport and metabolism in immune and vascular cells. Gln is transported into cells through several membrane transporters and modulates the entry and intracellular concentration of other AA through its interaction with Gln transporters. Following uptake, Gln is utilized in the cytosol to generate nucleotides, Asn, and glucosamines and may activate mTORC1. A majority of glutamine is converted to Glu and NH₃ by GLS1 in the mitochondria. NH₃ promotes cell survival by stimulating autophagy and the induction of HO-1. Glu that is exported to the cytosol is used to generate GSH and numerous non-essential amino acids via the action of a plethora of enzymes. The formed Arg is metabolized to NO by NOS, while Asp is used for nucleotide synthesis. Cytosolic Glu can also be converted back to Gln by GS. Mitochondrial glutamate is deamidated by GLUD1 or various aminotransferases to αKG, which supplies metabolites to the TCA cycle to fuel the generation of NADH, FADH₂, and ATP. Under hypoxic conditions, αKG supports the reductive carboxylation pathway yielding citrate, which is used for fatty acid synthesis. Gln-derived αKG also stimulates mTORC1 activity and collagen synthesis and influences the epigenetic modification of histones and DNA. The different colored shapes (ellipse, rhombus, pentagon, and quadrilateral) represent distinct Gln transporters. AA, amino acids; Gln, glutamine; Asn, asparagine; Glu, glutamate; GS, glutamine synthetase; GLS1, glutaminase-1; NH₃, ammonia; HO-1, heme oxygenase-1; GSH, glutathione; Pro, proline-; Orn, ornithine; Arg, arginine; Asp, aspartate; Ala, alanine; Ser, serine; Cys, cysteine; Gly, glycine; NO, nitric oxide; NOS, nitric oxide synthase; GLUD1, glutamate dehydrogenase 1; GOT1/2, glutamic-oxaloacetic acid transaminase 1/2; GPT1/2, glutamic-pyruvic transaminase 1/2; PSAT1, phosphoserine aminotransferase 1; αKG, alpha-ketoglutarate; TCA, tricarboxylic acid; NADH, nicotinamide adenine dinucleotide; FADH₂, flavin adenine dinucleotide; ATP, adenosine triphosphate; mTORC1, mammalian target of rapamycin complex 1.

Figure 2

Targeting Gln in COVID-19-mediated immune and endothelial dysfunction. SARS-CoV-2 lowers circulating levels of Gln by increasing GLS activity. The resulting decline in Gln compromises EC function and NO production by limiting cellular Arg levels. The loss of Gln also stimulates vascular inflammation, platelet aggregation, coagulopathy, and reduces the viability of ECs by restricting NO synthesis and the induction of HO-1. In addition, Gln deficiency causes a broad dysfunction of the immune system that worsens the severity of infection. The consumption of Gln in COVID-19 will also increase oxidative stress by reducing the synthesis of GSH and expression of HO-1. Collectively, these actions will promote vasospasm, thrombosis, and NETosis, resulting in vascular occlusion and multi-organ failure. Several strategies may be employed to target glutamine in COVID-19. Dietary supplementation with free or dipeptide forms of Gln provides a straightforward approach to restore circulating levels of Gln in SARS-CoV-2-infected patients. Alternatively, the direct administration of Gln metabolites (NH₃ or αKG) or downstream effectors of Gln (inhaled NO, NO donors, HO-1 inducers, CO donors, biliverdin, or bilirubin) provides a more selective avenue in correcting disturbances of Gln metabolism in patients with COVID-19. Downward pointing arrows indicate a decrease while upward pointing arrows indicate an increase. Gln, glutamine; Glu, glutamate; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; GLS, glutaminase; EC, endothelial cell; NO, nitric oxide; Arg, arginine; HO-1, heme oxygenase-1; GSH, glutathione; NETosis; the release of neutrophil extracellular traps; NH₃, ammonia; αKG, alpha-ketoglutarate; CO, carbon monoxide.