COVID-19 Vasculopathy: Mounting Evidence for an Indirect Mechanism of Endothelial Injury

Patients with coronavirus disease 2019 (COVID-19) who are critically ill develop vascular complications characterized by thrombosis of small, medium, and large vessels. Dysfunction of the vascular endothelium due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated in the pathogenesis of the COVID-19 vasculopathy. Although initial reports suggested that endothelial injury was caused directly by the virus, recent studies indicate that endothelial cells do not express angiotensin-converting enzyme 2, the receptor that SARS-CoV-2 uses to gain entry into cells, or express it at low levels and are resistant to the infection. These new findings, together with the observation that COVID-19 triggers a cytokine storm capable of injuring the endothelium and disrupting its antithrombogenic properties, favor an indirect mechanism of endothelial injury mediated locally by an augmented inflammatory reaction to infected nonendothelial cells, such as the bronchial and alveolar epithelium, and systemically by the excessive immune response to infection. Herein we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.

Following an initial outbreak of pneumonia in Wuhan, China, in December 2019,¹ coronavirus disease 19 (COVID-19) has spread rapidly worldwide, infecting more than 186 million people (Johns Hopkins Coronavirus Resource Center, https://coronavirus.jhu.edu, last accessed July 12, 2021). Caused by a new type of coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),² the COVID-19 pandemic has put a major strain on the healthcare systems, causing a global health crisis of unparalleled proportions in modern times.³ Although most patients have recovered from the infection, many experienced a severe form of the disease that requires hospitalization and intensive care, and >3.2 million people have died. Individuals at greatest risk for the fatal complications of COVID-19 have been the elderly and those with underlying conditions, such as lung disease, hypertension, obesity, and diabetes.⁴Clinical manifestations of COVID-19 in severely ill patients are adult respiratory distress syndrome and multiorgan system failure.^4,5 The clinical course of the disease can be complicated by vascular events, including thrombosis of small, medium, and large blood vessels and thromboembolism.^6,7 Although the primary target of SARS-CoV-2 is the respiratory and alveolar epithelium,⁸ the frequent occurrence of vascular complications in COVID-19 has led to the hypothesis that dysfunction of the endothelium, the inner lining of blood vessels, plays an important role in the progression of this disease into a debilitating and lethal condition.⁹ Two potential mechanisms have been hypothesized to explain how SARS-CoV-2 causes endothelial dysfunction and thrombosis. In the first scenario, SARS-CoV-2 directly infects the endothelium, disrupting its antithrombogenic and barrier properties. The second scenario invokes an indirect mechanism of endothelial injury mediated by the local and systemic inflammatory response to the viral infection.^10,11 In this article, we briefly review the vascular pathology of COVID-19 and critically discuss the proposed mechanisms by which SARS-CoV-2 damages blood vessels, including recent studies that challenge the viral infection of endothelium hypothesis and strongly favor an indirect, inflammation-driven mechanism of endothelial injury.     

Lysosomal Acid Lipase Deficiency Controls T- and B-Regulatory Cell Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants

Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune rejection and allows growth of human lung cancer cells in lal^−/− mice. In the lal^−/− lymph nodes, the percentages of both T- and B-regulatory cells (Tregs and Bregs, respectively) are increased, with elevated expression of programmed death-ligand 1 and IL-10, and decreased expression of interferon-γ. Levels of enzymes in the glucose and glutamine metabolic pathways are elevated in Tregs and Bregs of the lal^−/− lymph nodes. Pharmacologic inhibitor of pyruvate dehydrogenase, which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal^−/− lymph nodes. Blocking the mammalian target of rapamycin or reactivating peroxisome proliferator-activated receptor γ, an LAL downstream effector, reduces lal^−/− Treg and Breg elevation and PD-L1 expression in lal^−/− Tregs and Bregs, and improves human cancer cell rejection. Treatment with PD-L1 antibody also reduces Treg and Breg elevation in the lal^−/− lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain antitumor immunity.

Transplantable animal models, in which the relationship and interplay between malignant cells and immune cells can be studied, play a fundamental role in the study of oncoimmunology and development of therapeutic approaches to treat human cancer. Utilization of proper preclinical models accelerates development of immunotherapies and understanding of underlying mechanisms.^1,2 The host immune system determines the fate of invading cancer cells.³ In searching for appropriate immunosuppressive mouse models to study human cancer-derived xenografts, a genetic ablation mouse model (lal^−/−) of lysosomal acid lipase (LAL) was evaluated.⁴ LAL is a lipid metabolic enzyme catalyzing the hydrolysis of cholesteryl esters and triglycerides in the lysosome to generate free fatty acids and cholesterol.⁵ The hydrolyzed products are transported to the cytoplasm for either storage or utilization in membrane biogenesis, steroid hormone synthesis, and energy production. Although lal^−/− mice survive into adulthood, the metabolic defect of LAL deficiency leads to severe immunodeficiency, in which the lymphocyte levels are extremely low because of impaired development, maturation, and proliferation.⁶ The ratio of T-regulatory cells (Tregs) and myeloid-derived suppressive cells (MDSCs) is significantly increased, which suppresses T-cell function and directly stimulates tumor growth and invasion.6, 7, 8, 9, 10 More importantly, the compromised immunity accelerates growth and invasion of various murine tumor cells not only in syngeneic, but also allogeneic, lal^−/− mice.⁹ In this report, we show that immunodeficiency delays and reduces immune rejection of human cancer cells in lal^−/− mice. Herein, functional roles of Tregs and B-regulatory cells (Bregs) in the lal^−/− lymph nodes during failure of immune rejection, as well as the abnormal expression and function of PD-L1 in lal^−/− Tregs and Bregs in association with the metabolic switch toward glycolysis and glutamine utilization are systematically evaluated. Furthermore, the functional roles of mammalian target of rapamycin (mTOR) and peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor are characterized in Tregs and Bregs of the lal^−/− lymph nodes during human cancer cell rejection. We conclude that Tregs and Bregs in the lal^−/− lymph nodes play critical roles in suppression of immune rejection of human cancer growth, together with other cell types [eg, MDSCs and endothelial cells (ECs)], in lal^−/− mice. Therefore, the immunodeficient lal^−/− mouse model serves as a potential preclinical model that can be used for clinical human cancer studies.