Metabolic Syndrome. Particularities During SARS-CoV-2 Infection

Rezumat The COVID-19 pandemic is a significant public health crisis as the coronavirus continues to rapidly spread with long-term socioeconomic consequences. Another malady, although non-transmissible, also a significant health hazard is the metabolic syndrome, which has widespread globally, being classified as an epidemic as the western lifestyle expands worldwide. The SARS-CoV-2 causes systemic inflammation similar to obesity; nevertheless, the coronavirus causes an unregulated rise in cytokine secretion, resulting in multiple organ failures and death. Increas-ing evidence demonstrates that obesity aggravates the COVID-19 disease and its mortality, the four most prevalent comorbidities of COVID-19 being hypertension, diabetes, cardiovascular, and respiratory disease, all of them tightly associated with obesity. This paper reviews the physiopathological processes that constitute the metabolic syndrome and the molecular mechanisms through which the coexistence of MetS can contribute to the pathogenicity of COVID-19 and an unfavorable outcome of the disease.


INTRODUCTION
Since the emergence of the first cases of infection in Wuhan, China, in December 2019, the SARS-CoV-2 virus has spread globally, and on March 11, 2019, the WHO classified the SARS-CoV-2 infection as a pandemic. A WHO report on SARS-CoV-2 indicates that as of 01.05.2021, there were over 155 million cases of infections and over 3 million deaths. The SARS-CoV-2 pandemic poses a devastating challenge to health systems around the world and the global economy¹.
Metabolic syndrome (MS), also known as X syndrome, is defined by the WHO as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. MetS is clinically diagnosed by the simultaneous presence of three or more of these pathologies, which are correlated due to overlapping metabolic pathways and pathophysiological mechanisms that coincide². MS is a plethora of cardiovascular risk factors, including abdominal obesity, high blood pressure, impaired glucose tolerance, atherogenic dyslipidemia, pro-thrombotic status and pro-inflammatory status² , ³.
Obesity is one of the leading causes of MetS and can contribute to the development of type 2 diabetes (T2DM), stroke, cardiovascular disease, and hypertension. According to the WHO, the obesity rate has tripled since 1975, with over 650 million adults being obese in 2016. Surprisingly, by 2050 the overall global obesity rate is expected to exceed the majority of the adult population⁴ , ⁵.
Research demonstrates a strong clinical correlation between MetS and COVID-19 as increased hospitalization, severe progression, and poor clinical outcomes and mortality rates seem to correlate with risk factors such as obesity, hypertension, DM, cardiovascular disease⁶.

Parameter
Categorical cut-points WHO acknowledges two levels of abdominal obesity in Europids (men of European descendence from the Middle East, Eastern Mediterranean region, and Sub-Saharan Africa) depending on the risk for metabolic complications. Increased risk occurs at waist circumferences of ≥94 cm in men and ≥80 cm in women, but the risk is substantially higher at ≥102 cm in men and ≥88 cm in women. The higher thresholds are used to define abdominal obesity in the United States, Canada, Europe and are also used as the waist circumference cut points to diagnose MetS⁸.

ADIPOSE TISSUE IN OBESITY
The adipose tissue (AT) has a dynamic endocrine role as it secrets a diversity of cell signaling cytokines, Healthy adipose tissue has a complex and heterogeneous composition that includes adipocytes and several types of stromal cells, including fibroblasts, adipose-derived stem cells (ASCs), endothelial cells, and a variety of immune cells, such as resident macrophages, mast cells, monocytes, dendritic cells, natural killer cells, B cells, T cells, neutrophils, and eosinophils⁹.
Obesity remodels the adipose tissue through hypertrophy and hyperplasia of the adipocytes, leading to hypoxia of the adipose tissue, apoptosis of adipocytes, and an increased secretion of inflammatory adipokines, cytokines, and chemokines⁶. This results in a massive infiltration of proinflammatory cytokines that stimulate lipolysis and fuel insulin resistance, leading to adipocyte dysfunction and systemic disruptions of metabolism¹º. Ergo, the AT develops a local low-grade inflammatory microenvironment that attracts M1 inflammatory macrophages, T-cells, B-cells, neutrophils, and mast cells, whereas populations of type 2 helper T-cells (TH2), macrophage M2, and regulatory T-cells (Treg) decrease as the levels of obesity progress⁶. As AT expands in obesity, the regulatory anti-inflammatory, immune state maintained by immunoregulatory cytokines including interleukin-4 (IL-4), IL-5, IL-10, IL-13, and IL-33 converts to a highly inflammatory state causing the secretion of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α), IL-1β, interferon γ (IFN-γ), and IL-6, promoting a local as well as chronic systemic inflammation and metabolic dysfunction¹¹. The secretion of these proinflammatory cytokines is mediated by the NLRP3 inflammasome, which plays a critical role in immune responses, glucose homeostasis, lipid metabolism, and adipocyte functions¹².

NLRP3 INFLAMMASOME, METABOLIC DISORDERS, AND PYROPTOSIS
The NLRP3 inflammasome is a large multimolecular complex present in the cytosol of stimulated immune cells such as monocytes, macrophages, and dendritic cells. Activation of NLRP3 inflammasome is the most significant component of the innate immune response, crucial in the host defense against pathogens such as bacteria, fungi, or viruses. On the other hand, the NLRP3 inflammasome has been associated with met-abolic and inflammatory conditions such as T2DM, insulin resistance, atherosclerosis, obesity, gout, and neurodegenerative diseases¹³ , ¹⁴. Once activated, the NLRP3 inflammasome will induce pyroptosis, an inflammatory form of programmed cell death through the assembly of plasma membrane pores by members of the gasdermin (GSDM) protein family into the macrophage cell membrane as a consequence of inflammatory caspase activation. This process disrupts the osmotic potential of the cell membrane and releases cytosolic content causing systemic dissemination of pro-inflammatory molecules¹⁴.
Activation of the NLRP3 inflammasome impacts the development of T2DM and its complications, as overexpression of IL-1β consequently causes dysregulation of glycemic control. In hepatocytes and adipocytes, the IL-1β cytokine interferes with insulin signaling, inhibiting insulin-induced glucose uptake, suppressing lipogenesis, and reducing adiponectin release. The pancreatic islets are affected by the IL-1β cytokine, which reduces insulin secretion, impairs β-cell replication, and increases β-cell apoptosis. Furthermore, IL-1β promotes tumor necrosis factor-alpha (TNFα), a cytokine known to increase insulin resistance¹⁵ , ¹⁶.
The NLRP3 inflammasome is also involved in the pathogenesis of atherosclerosis, which is characterized by an intricate interaction between macrophages, endothelial cells, and smooth muscle cells¹³. The endothelium controls vascular homeostasis by preserving a careful balance between vasodilators and vasoconstrictors secretion and producing bioactive mediators regulating vascular tone, permeability, proliferation, and smooth muscle cell migration, leukocyte migration, and platelet adhesion and aggregation¹⁷. Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide and a significant consequence of MetS.18 Impaired lipid metabolism, specifically elevated levels of plasma LDL-cholesterol contributes to the formation of atherosclerotic plaques. Intracellular cholesterol-carrying lipoprotein (oxLDL) is converted into cholesterol crystals causing NLRP3 inflammasome activation. Normal vascular smooth muscle cells become dysfunctional due to the release of mature IL-1β that leads to platelet aggregation and activation of inflammatory cells. Consequently, IL-1β and IL-18 secretion skyrocket, disrupting endothelial hemostasis by aggravating and amplifying the inflammatory response and contributing to the rising morbidity of cardiovascular and cerebrovascular diseases¹³.

COVID-19, NLPR3 INFLAMMASOME AND PYROPTOSIS
The agent responsible for COVID-19 is known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is an enveloped single-stranded positive-sense RNA virus studded with spike (S), membrane (M), and envelop (E) proteins¹⁴. SARS-CoV-2 enters target cells via its viral spike (S) protein, which binds to its functional receptor human angiotensin-converting enzyme 2 (ACE2). The ACE2 protein is present in arterial smooth muscle cells in all organs, including oral and nasal mucosa, nasopharynx, stomach, colon, liver, kidney, and brain, with a unique expression of ACE2 protein on lung alveolar epithelial cells, small intestine enterocytes, and endothelial cells¹⁹. ACE2 is also highly expressed in AT, and its expression increases with obesity, making AT a potential target organ for SARS-CoV-2 and its viral reservoir²º. NLRP3 Inflammasome activation triggered by viral internalization induces pyroptosis and results in a massive release of TNFα, IFNγ, IL-1 β, IL-8, MCP-1, and IP-10 as seen in the acute phase of COVID-19 patients. It has been suggested that the viral reservoir could act as a catalyst, boosting intense inflammation, fueling an exacerbated immune response, damaging tissues, and causing multi-organ failure, all of which are severe COVID-19 complications⁶. SARS-CoV-2 depends on furin-mediated pre-cleavage of its spike protein at the S1/S2 site, proteolysis that initiates the process of cellular entry. Furin is also highly expressed in obese AT as well as during adipogenesis. Furin not only supports the entry of SARS-CoV-2 into cells by priming the spike protein but also the release of new viral particles, allowing them to enter circulation and invade the neighboring cells⁶,²¹.

OBESITY AND CYTOKINE STORM IN COVID-19
Like obesity, SARS-CoV-2 also induces systemic inflammation, but it can determine an aggressive immune response known as cytokine storm or cytokine release syndrome in critically ill patients. The cytokine storm is characterized by an uncontrolled increase of cytokine secretion, with detrimental effects causing multiple organ failure followed frequently by death. The pre-existing systemic inflammatory state in obese patients can be boosted or accelerated during SARS-CoV-2 infection by activating the NLRP3 inflammasome and the release of pro-inflammatory cytokines through Gasdermin-pores after pyroptosis¹⁴.
Cytokine storm appears to be important in COVID-19 patients when it comes to the pathogenesis of several severe forms of the disease: acute respiratory distress syndrome, thromboembolic events such as acute ischemic strokes or myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult)¹⁴.

MECHANISMS FOR INCREASED SARS-COV-2 INFECTION SEVERITY IN METS
Several studies have shown a close connection between COVID-19 and MetS. Obese COVID-19 patients with impaired metabolic health have a higher hospitalization rate, a faster progression, and worse health outcomes. At least five aspects link obesity, diabetes, and COVID-19: viral load, immune response, alveolar dysfunction, endothelial dysfunction, and coagulopathy⁶. SARS-CoV-2 viral load may be increased through an effective cellular entry mediated by ACE2 receptors. An overexpression of ACE2 was detected in the AT of obese patients and the lung, kidney, and heart tissue of diabetic mice²².
The efficient clearance of viral load in all viral infections depends on the coordinated actions of the innate and adaptive immune system. Obesity and diabetes impair the immune response, and both are correlated to chronic low-level inflammation, decreased NK cell function, and deregulated numbers of CD4+ and CD8+ T cells, all of which could lead to a delayed immune response and sustained hyper inflammation in COVID-19 patients²².
Individuals with T2DM have substantially lower pulmonary function parameters such as forced vital power, total lung capacity, alveolar membrane permeability, and alveolar gas exchange²². Obesity has a wide range of adverse effects on lung function, weakening the lung defenses against SARS-CoV-2. The respiratory volumes are decreased, the systemic inflammation alters microvascular permeability, damaging endothelial cells and leading to airway obstruction. Expanding AT around the pulmonary artery alongside systemic inflammation, insulin resistance, and oxidative stress can lead to pulmonary arterial hypertension⁶ , ²³.
Patients with diabetes during SARS-CoV-2 infection are more likely to develop endothelitis due to increased vascular lesions, endothelial inflammation, and vasoconstriction correlated with previous endothelial dysfunction.22 SARS-CoV-2 infection could initiate endothelial inflammation in several organs, and pyroptosis may have an essential role in endothelial cell injury and host inflammatory response contributing to the cytokine storm and pulmonary lesions⁶.
Obesity promotes the development of hypertension by damaging the endothelium and causing systemic inflammation. Furthermore, morbidly obese patients have higher serum renin levels, angiotensinogen, ACE, Ang II, and aldosterone, activating the renin-angiotensin-aldosterone mechanism leading to the development of hypertension and cardiovascular disease²⁴. The myocardium is also affected by SARS-CoV-2-induced endothelitis and microvascular dysfunction. The cytokine storm observed in severe COVID-19 cases is thought to cause vascular inflammation and atheroscle-Metabolic Syndrome. Particularities During SARS-CoV-2 Infection rotic plaque instability, and myocardial inflammation. Therefore, patients with COVID-19 can develop cardiovascular complications such as acute coronary syndrome, an acute myocardial injury without obstructive coronary artery disease, arrhythmias, heart failure, pericardial effusion, or thromboembolic complications²⁵.
Severely ill COVID-19 patients are often associated with increased systemic coagulation and obesity as well as diabetes are characterized by a prothrombotic status²⁶. In obesity, the hypercoagulable state is correlated with the overexpression of multiple proteins associated with coagulation like thrombin, fibrinogen, coagulation factors (FXa, FVIIa, and FV), and activated protein C in diverse cell types including adipocytes, endothelial cells, and vascular smooth muscle cells²⁷. COVID-19 disease in patients with obesity and impaired metabolic health exacerbates the clotting disorders, as acute hyperglycemia and hyperinsulinemia were shown to trigger coagulation and fibrinolytic activity during the inflammatory response²².

CONCLUSIONS
The simultaneous presence of underlying chronic conditions such as hypertension, obesity, or cardiovascular diseases together with altered ACE2 receptor expression, immune dysregulation, alveolar and endothelial dysfunction, and increased systemic coagulation may put individuals with metabolic syndrome at risk for severe forms of COVID-19.
Compliance with ethics requirements: The authors declare no conflict of interest regarding this article. The authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008(5), as well as the national law. Informed consent was obtained from all the patients included in the study.