COVID-19 News: The Role of Glutamine Deficiency in Immune and Endothelial Cell Dysfunction in COVID-19 and Potential Therapeutic Strategies
: The SARS-CoV-2 pandemic has led to the death of almost 7 million people worldwide. Despite vaccinations and new antiviral drugs significantly reducing COVID-19 cases, there remains a need for additional therapeutic strategies to combat this deadly disease. One potential target is the deficiency of circulating glutamine observed in patients with COVID-19, which associates with disease severity according to researchers from the University of Missouri – USA.
Glutamine, a semi-essential amino acid, is metabolized to various metabolites that modulate immune and endothelial cell function. levels.
Glutamine and Its Importance in Immune Function and Vascular Health
Glutamine is a versatile molecule involved in intermediary metabolism, interorgan nitrogen exchange, ammonia detoxification, and pH homeostasis. It is a major regulator of immune function, influencing both myeloid and lymphoid cells.
Clinical studies indicate that glutamine supplementation improves immune function in patients with burn injury, gastrointestinal surgical operations, and critically ill patients, reflected by increased lymphocyte function and reduced infectious complications, hospital stay, morbidity, and mortality. Favorable clinical outcomes with glutamine have also been reported in patients undergoing major abdominal surgery or receiving bone marrow transplants.
Furthermore, glutamine plays a fundamental role in preserving vascular health by modulating endothelial cell (EC) and smooth muscle cell (SMC) function. A reduced availability of glutamine may impair immune function and increase susceptibility to infections and vascular disease.
As covered in various past studies and COVID-19 News
reports, metabolic analyses have identified low levels of glutamine in COVID-19 patients, suggesting that the rewiring of glutamine metabolism by SARS-CoV-2 may contribute to poor outcomes in these patients.
Role of Glutamine in Immune Cells
Glutamine plays a significant role in regulating the function of immune cells. The production of inflammatory cytokines by monocytes and macrophages is dependent on the availability of glutamine, which is also required for maximal cytokine synthesis and phagocytosis by macrophages. Nitric oxide (NO) generation by activated macrophages requires glutamine, which provides cells with additional substrate (arginine) for NO synthesis. Importantly, NO has been reported to mitigate the replication of SARS-CoV-2.
In addition to macrophages, glutamine also modulates the function of lymphocytes. Depletion of glutamine blocks the proliferation of activated T lymphocytes and their ability to release interleukin-2 and interferon-γ (IFNγ).
Glutamine is also required for the growth, plasma cell differentiation, and antibody production of B lymphocytes. Moreover, glutamine deficiency or glutaminase (GLS1) inhibition inhibits clonal expansion and activation of CD8 T lymphocytes, which may account for the exhaustion and depletion of these cells in patients with COVID-19.
Role of Glutamine in Vascular Health&l
Considerable evidence indicates that glutamine contributes to vascular health. Cross-sectional clinical studies found that plasma glutamine or the glutamine/glutamate ratio is inversely related to blood pressure, hypertriglyceridemia, and insulin resistance, while plasma glutamate concentrations are linked to adverse vascular and metabolic indices.
A prospective study noted that the circulating glutamine/glutamate ratio is coupled to a reduced risk of cardiovascular disease, while blood glutamate is associated with an elevated risk, especially for stroke.
The mechanism(s) underlying the protective effect of glutamine in the circulation is not fully known. However, the ability of glutamine to directly influence the property of ECs is significant, as the endothelium plays a critical role in maintaining vascular homeostasis and regulating immune responses. Several mechanisms have been proposed to explain the protective effect of glutamine on endothelial cells (ECs) and immune function:
-Nitric Oxide (NO) Production
Glutamine may enhance endothelial function by promoting nitric oxide (NO) production. NO is a vital signaling molecule produced by ECs that maintains vascular tone, inhibits platelet aggregation, and regulates leukocyte adhesion. Glutamine has been shown to stimulate the production of NO in ECs through the upregulation of endothelial nitric oxide synthase (eNOS) expression and activity.
Glutamine also exhibits antioxidant properties, which can help protect ECs from oxidative stress. Reactive oxygen species (ROS) generated during inflammation can cause damage to endothelial cells and compromise vascular integrity. Glutamine may protect ECs by scavenging free radicals, upregulating antioxidant enzymes, and promoting the synthesis of the antioxidant molecule glutathione.
Glutamine can modulate immune responses and exert anti-inflammatory effects by regulating the activation of nuclear factor-kappa B (NF-κB), a transcription factor involved in the expression of inflammatory genes. Glutamine has been shown to inhibit NF-κB activation, leading to a decrease in the production of pro-inflammatory cytokines and adhesion molecules in ECs. This can help maintain endothelial integrity and reduce excessive immune responses.
-Stabilization of Endothelial Barrier Function
Glutamine may help maintain endothelial barrier function by influencing the expression and distribution of tight junction proteins, which regulate paracellular permeability. The preservation of tight junctions can prevent the excessive leakage of plasma proteins and immune cells into the surrounding tissues, reducing tissue edema and inflammation.
Modulation of Immune Cell Function
In addition to its effects on ECs, glutamine plays a crucial role in the metabolism and function of immune cells, including lymphocytes, macrophages, and neutrophils. Glutamine is necessary for energy production, proliferation, and the production of cytokines and other effector molecules in immune cells. By modulating immune cell metabolism, glutamine can influence the balance between pro-inflammatory and anti-inflammatory responses, ultimately affecting the outcome of the infection.
In summary, glutamine's protective effects on endothelial cells and immune function may be attributed to several mechanisms, including the promotion of nitric oxide production, antioxidant and anti-inflammatory effects, stabilization of endothelial barrier function, and modulation of immune cell function. Further research is needed to elucidate the precise molecular mechanisms through which glutamine exerts these beneficial effects and to develop targeted therapeutic strategies for COVID-19 patients with glutamine deficiency.
To counteract the negative effects of glutamine deficiency in COVID-19 patients, several strategies targeting glutamine metabolism have been proposed. These include glutamine supplementation, modulation of glutaminase activity, and manipulation of downstream glutamine metabolites and signaling pathways.
Glutamine supplementation is a straightforward approach to restore circulating glutamine levels in COVID-19 patients. Several clinical trials have demonstrated the benefits of glutamine supplementation in critically ill patients, improving immune function, reducing infectious complications, and shortening hospital stays. In the context of COVID-19, glutamine supplementation may help restore immune and endothelial cell function, mitigate inflammation, and prevent the development of vascular occlusion and multi-organ failure. However, it is essential to closely monitor glutamine supplementation to avoid excessive glutamine levels, which may lead to hyperammonemia, a detrimental condition associated with neurological complications.
Modulation of Glutaminase Activity
Targeting glutaminase (GLS) activity may help restore glutamine levels and improve outcomes in COVID-19 patients. Inhibition of GLS activity can prevent the excessive catabolism of glutamine, thereby maintaining sufficient levels of this essential amino acid in the circulation. However, given the diverse roles of glutaminase in various cell types, careful consideration of dose and selectivity is required when modulating GLS activity to avoid unintended consequences.
Manipulation of Downstream Glutamine Metabolites and Signaling Pathways
Another strategy to restore the effects of glutamine deficiency in COVID-19 patients is to manipulate downstream glutamine metabolites and signaling pathways. This includes the administration of α-ketoglutarate, a critical intermediate in glutamine metabolism, which has been shown to rescue endothelial cell function in the absence of glutamine. Additionally, targeting the ammonia-heme oxygenase-1-carbon monoxide signaling axis, which plays a crucial role in promoting vascular health, may provide therapeutic benefits in COVID-19 patients with glutamine deficiency.
In conclusion, the COVID-19 pandemic has highlighted the importance of glutamine in immune and endothelial cell function. Glutamine deficiency, observed in COVID-19 patients, contributes to immune and vascular cell dysfunction, leading to severe infection, inflammation, oxidative stress, and coagulopathy. Targeting glutamine metabolism, either through supplementation or by modulating its downstream metabolites and signaling pathways, may represent a promising therapeutic approach in conjunction with antiviral drugs. This strategy has the potential to restore immune and endothelial cell function, prevent vascular occlusion, and improve clinical outcomes in patients with COVID-19. Further research is needed to determine the optimal dosing and timing of these interventions, as well as their safety and efficacy in diverse patient populations.
The study review on Glutamine role in COVID-19’s Immune and Endothelial Dysfunction was published in the peer reviewed International Journal of Molecular Sciences.
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