Targeting Arginine in COVID-19: History
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Subjects: Immunology
Contributor:
William Durante

Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19. 

  • COVID-19
  • arginine
  • arginase
  • nitric oxide synthase
  • immunopathology
  • endothelial dysfunction
  • thrombosis
  • vascular disease

1. Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. This disease is a substantial threat to human health with over 418 million cases worldwide and over 5.8 million confirmed deaths, as of February 2022 [1]. SARS-CoV-2 is transmitted primarily by respiratory droplets; however, direct aerosol contact with contaminated sources and fecal–oral transmission are also possible [2]. The virus infects the host by targeting airway and alveolar epithelial cells in the lung that express the surface receptor angiotensin-converting enzyme 2 (ACE2). The coronavirus enters host cells via its surface spike protein that binds to ACE2 through its receptor binding domain where it is proteolytically activated by human proteases allowing for cell entry. Subsequent viral replication and release causes the host cell to undergo pyroptosis and emit damage-associated molecular patterns, including ATP and nucleic acid, which triggers the discharge of proinflammatory cytokines and chemokines. However, not all exposures to SARS-CoV-2 lead to symptomatic infection. Among infected individuals that develop symptoms, an estimated 80–85% experience mild flu-like symptoms, such as fever, cough, myalgia, and fatigue, and most recover in a few days or weeks [3]. The remaining 15–20% of patients suffer more severe symptoms that may require hospitalization and treatment in an intensive care unit. Overall mortality rates vary greatly depending on risk factors but lie between 0.3 and 3.0% of all infected individuals [4]. The markedly heterogenous presentation of COVID-19 likely reflects the degree of viral infection and the activity of the host’s immune system [5]. In most cases, the destruction of lung cells by SARS-CoV-2 initiates a local immune response that promotes the release of anti-viral cytokines and primes adaptive T and B cell immune responses, leading to the resolution of the infection. Alternatively, in some instances, a dysfunctional immune response occurs where a proinflammatory feedback loop is established, eliciting a cytokine storm that mediates widespread lung inflammation resulting in severe pneumonia and acute respiratory distress syndrome (ARDS). Moreover, this heightened systemic inflammatory state induces endothelial cell (EC) dysfunction and vascular smooth muscle cell (SMC) proliferation and migration, precipitating a constellation of vascular complications, such as stroke, ischemia, and thrombosis, which contribute to multi-organ failure and the high mortality rate in COVID-19 [6].
The metabolism of arginine serves as a key regulator of innate and adaptive immunity [7][8][9][10][11]. Arginine catabolism in myeloid cells is largely driven by nitric oxide (NO) synthase (NOS) and arginase (ARG), and the differential regulation of these enzymes augments or diminishes the immune response. In a similar fashion, the divergent modulation of the activity of these two enzymes dictates vascular cell function, where NOS serves to maintain vascular health while ARG is linked to EC dysfunction and vascular disease [12][13][14][15][16][17][18]. Intriguingly, ARG expression is upregulated in patients with COVID-19 in a disease-dependent manner, suggesting that the rewiring of arginine metabolism by ARG may contribute to poor outcomes in COVID-19 patients [19].

2. Targeting Arginine in COVID-19

There is a growing appreciation for the role of amino acids in regulating immune and vascular cell function. Substantial evidence suggests that the metabolism of arginine is altered in COVD-19. In particular, the bioavailability of arginine is seriously compromised in COVID-19 patients and there is an upregulation of ARG1 that skews the metabolism of arginine away from the synthesis of NO (Figure 1). By limiting the production of NO, ARG1 depresses EC survival and function, immune responses, and augments platelet aggregation and inflammation, leading to vasoconstriction and thrombosis. In addition, the reduction in NO synthesis, coupled with the ARG1-mediated shunting of arginine toward polyamine and proline synthesis, will stimulate vascular SMC proliferation, migration, and collagen deposition (resulting in arterial thickening), fibrosis, and stiffening. Collectively, these actions will promote vascular occlusion and organ failure.
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Figure 1. Targeting arginine in COVID-19-induced immune and vascular dysfunction. There is an upregulation of arginase 1 (ARG1) by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that diminishes circulating arginine levels and shunts the metabolism of arginine away from the synthesis of nitric oxide (NO) by NO synthase toward the production of ornithine, which is subsequently converted to polyamines and proline via the action of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT), respectively. The induction of ARG1 causes immune malfunction, inflammation, and endothelial cell (EC) death and dysfunction, and stimulates vascular smooth muscle cell (SMC) proliferation, migration, collagen synthesis, and platelet aggregation, leading to vasoconstriction, thrombosis, arterial thickening, fibrosis, and stiffening. Collectively, these actions will promote vascular occlusion and organ failure. Several strategies may be used to target arginine in COVID-19. Dietary supplementation with arginine or citrulline provides a forthright approach to restore circulating levels of arginine in SARS-CoV-2-infected patients. Alternatively, the use of ARG inhibitors provides a more selective modality in correcting disturbances of arginine metabolism in COVID-19. In addition, the direct administration of arginine metabolites (inhaled NO, NO donors, inorganic nitrates, and homoarginine) or NO-potentiating drugs [soluble guanylate cyclase (sGC) activators or stimulators, and phosphodiesterase type 5 (PDE5) inhibitors] affords another avenue in treating COVID-19 patients. eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase.
Several strategies can be employed to correct the disturbances of arginine metabolism in COVID-19. One straightforward approach involves amino acid therapy to target the deficiency of arginine in patients with COVID-19. In this regard, numerous experimental and clinical studies have shown that enteral or parenteral administration of arginine ameliorates endothelial function in a host of vascular diseases [12][20][21]. Of concern, arginine is a key nutrient in the lifecycle of many viruses, and the replenishment of this amino acid may stimulate SARS-CoV-2 replication. Indeed, arginine depletion has been proposed as a potential treatment for COVID-19 [22][23]. However, given that circulating levels of arginine are already low in COVID-19, a further reduction may potentially exacerbate the illness. Moreover, interim results from a randomized clinical trial found that the addition of arginine to standard therapy in patients hospitalized with COVID-19 reduced respiratory support and in-hospital stay relative to placebo-treated controls, supporting the use of arginine in the treatment of COVID-19 [24]. Of note, the dose of arginine (1.66 g twice per day) used in the research was rather low and it is not known whether it increased arginine availability in these patients. Owing to the extensive metabolism of orally administered arginine by the splanchnic circulation, higher doses of arginine may be required to fully restore circulating arginine levels [25]. Since it has a more favorable pharmacokinetic profile, the use of citrulline should also be considered as it is more efficient than arginine in raising systemic arginine availability [26]. Interestingly, the supplementation with vitamin D, i.e., another dietary compound that regulates immune and vascular cell function, has also been proposed for COVID-19 patients, further highlighting the potential use of nutraceuticals in treating this infection [27][28][29].
A potential concern with arginine replenishment therapies is that arginine may be channeled via maladaptive pathways (ARG1) to worsen immune and vascular cell dysfunction in COVID-19 [30][31]. In addition, arginine may elicit pleiotropic effects that aggravate cardiovascular disease [20][21][22][23][24][25][26][27][28][29][30][31][32]. In this respect, the use of ARG inhibitors may provide a more selective approach in treating COVID-19 patients. Several highly potent ARG inhibitors have been developed and their therapeutic potential has been validated in several small clinical studies. Intrabrachial infusions of an ARG inhibitor increases local forearm endothelium-dependent vasodilation in patients with familial hypercholesterolemia, type 2 diabetes, and coronary artery disease, as well as in healthy elderly subjects [33][34][35]. Similarly, the administration of a combination of ARG inhibitors in dorsal forearm skin by intradermal microdialysis significantly augments local cutaneous vasodilation in patients with arterial hypertension [36]. Importantly, ARG inhibitors are well tolerated and exhibit no reported toxicities with few non-specific actions [37][38]. Currently, two promising ARG inhibitors are used in clinical trials: Numidargistat for cancer immunotherapy and CB-280 for cystic fibrosis treatment [39]. Curiously, many comorbidities which increase the risk of infection and poor outcomes in COVID-19, such as diabetes, hypertension, cardiovascular disease, chronic kidney disease, and old age, are associated with endothelial dysfunction and high ARG activity [9][10][11][12][13][14][15][16][17][18][40]. The elevation in ARG expression in these highly vulnerable patient groups, who are likely to respond favorably to strategies targeting ARG, may explain the adverse outcomes in these patients.
The direct administration of arginine metabolites provides another therapeutic modality for treating patients with COVID-19. Inhalation of NO is under study in numerous COVID-19-related clinical trials (see [41]). These interventional studies with NO aim to reverse virus burden, bronchoconstriction, inflammation, and respiratory failure; treat and prevent progression in patients with mild and moderate disease; and act as a protective option for healthcare providers. One small study found that inhaled NO is well tolerated and might benefit pregnant patients with hypoxic respiratory failure [42], while other minor trials suggested that inhaled NO therapy may prevent the progression of hypoxic respiratory failure in spontaneously breathing COVID-19 patients [43][44]. A case report also determined that inhaled NO ameliorates dyspnea and fatigue in a single patient with idiopathic pulmonary hypertension that had been diagnosed with COVID-19 [45]. Single-center prospective studies also reported that inhaled NO increases ventilation/perfusion match in patients with severe pneumonia [46][47]. However, other studies found that inhaled NO fails to restore arterial oxygenation in COVID-19 patients with severe hypoxemia [48][49]. Similarly, a larger multicenter study showed that inhaled NO via a high-flow nasal cannula did not reduce oxygen requirements in COVID-19 patients with respiratory failure or the need for mechanical ventilation [50]. The future release of ongoing clinical trials may further clarify the utility and dosing requirements of inhaled NO in COVID-19 patients.
The use of donor molecules provides another avenue for the delivery of NO. Numerous NO-releasing molecules that possess unique biophysical properties, half-life, and release kinetics that are dictated by specific stimuli (such as light, heat, and pH) have been developed [51]. In addition, the incorporation of NO into polymers through micelles, dendrimers, star-shaped polymers, and polymeric nanoparticles permits the liberation of NO in a more continuous fashion [52]. Recent clinical studies have also highlighted the utility of oral nitrate therapy in raising circulating levels of NO [53]. Dietary or intravenously administered inorganic nitrate is reduced to NO via the entero-salivary circulation. Nitrate supplementation with beetroot juice improves endothelial function and blood pressure in patients with hypertension and shows promise in conditions of myocardial infarction, heart failure, stroke, and pulmonary hypertension [54][55]. Epidemiological studies have also implicated low levels of the arginine metabolite homoarginine as a risk factor for cardiovascular disease [55]. In addition, several experimental studies suggest that homoarginine plays a direct protective role in the circulation, possibly by promoting NO synthesis by serving as a NOS substrate and/or an ARG inhibitor. An early phase one clinical trial in healthy volunteers found that oral supplementation with homoarginine elevates plasma homoarginine concentration without any adverse effects, paving the way for larger prospective studies in patients with cardiovascular disease [56]. Given that homoarginine levels are depressed in COVID-19 patients, the oral administration of homoarginine may be beneficial in this patient population [57].
Aside from elevating circulating levels of NO, one can also augment the biological activity of the gas. Since many of the beneficial effects of NO in the circulation are mediated by the activation of soluble guanylate cyclase (sGC) and the subsequent rise in intracellular cyclic guanosine monophosphate (cGMP), schemes targeting this NO signaling pathway may be beneficial [58]. Highly potent activators of sGC which activate the enzyme in oxidized or heme-free form have been developed. In addition, sGC stimulators that bind to the heme-containing form of sGC and potentiate the effects of endogenous NO are available. In this respect, the sGC stimulator riociguat is used to clinically treat pulmonary arterial hypertension. Finally, several clinically prescribed inhibitors of phosphodiesterase type 5, which specifically hydrolyses cGMP, are commonly used in the treatment of erectile dysfunction and pulmonary arterial hypertension and may be useful in treating the respiratory and vascular complications associated with COVID-19.

This entry is adapted from the peer-reviewed paper 10.3390/metabo12030240

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