Endothelial Cells in Emerging Viral Infections

Abstract

There are several reasons to consider the role of endothelial cells in COVID-19 and other emerging viral infections. First, severe cases of COVID-19 show a common breakdown of central vascular functions. Second, SARS-CoV-2 replicates in endothelial cells. Third, prior deterioration of vascular function exacerbates disease, as the most common comorbidities of COVID-19 (obesity, hypertension, and diabetes) are all associated with endothelial dysfunction. Importantly, SARS-CoV-2's ability to infect endothelium is shared by many emerging viruses, including henipaviruses, hantavirus, and highly pathogenic avian influenza virus, all specifically targeting endothelial cells. The ability to infect endothelium appears to support generalised dissemination of infection and facilitate the access to certain tissues. The disturbed vascular function observed in severe COVID-19 is also a prominent feature of many other life-threatening viral diseases, underscoring the need to understand how viruses modulate endothelial function. We here review the role of vascular endothelial cells in emerging viral infections, starting with a summary of endothelial cells as key mediators and regulators of vascular and immune responses in health and infection. Next, we discuss endotheliotropism as a possible virulence factor and detail features that regulate viruses' ability to attach to and enter endothelial cells. We move on to review how endothelial cells detect invading viruses and respond to infection, with particular focus on pathways that may influence vascular function and the host immune system. Finally, we discuss how endothelial cell function can be dysregulated in viral disease, either by viral components or as bystander victims of overshooting or detrimental inflammatory and immune responses. Many aspects of how viruses interact with the endothelium remain poorly understood. Considering the diversity of such mechanisms among different emerging viruses allows us to highlight common features that may be of general validity and point out important challenges.

Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs

“…These changes can lead to acute respiratory distress syndrome (ARDS) and multiorgan failure, [5][6][7][8][9] a reflection of renin-angiotensin and endothelial dysfunction that is central to COVID-19's pathogenesis. 2,3,[10][11][12][13][14][15][16] Endothelial damage is directly responsible for microvascular immunothrombosis and thromboembolism seen in the lungs and other organs of many COVID-19 patients who have died. [17][18][19][20][21][22]…”

“…The pathogenesis of COVID-19 is characterized (among other things; see below) by endothelial dysfunction. 2,3 Several inexpensive drugs like statins, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have immunometabolic activities that maintain or restore endothelial cell function. 4 For this reason, we have undertaken an observational study to determine whether in-hospital treatment with these drugs could improve COVID-19 patient survival.…”

Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and/or ARBs

“…COVID-19 is characterized by severe inflammation, altered interferon, complement and epigenetic responses and dysregulation of innate and adaptive immunity. These changes can lead to acute respiratory distress syndrome (ARDS) and multi-organ failure [5][6][7][8][9], a reflection of renin-angiotensin and endothelial dysfunction that is central to COVID-19's pathogenesis [2,3,[10][11][12][13][14][15][16]. Endothelial damage is directly responsible for microvascular immunothrombosis and thromboembolism seen in the lungs and other organs of many COVID-19 patients who have died [17][18][19][20][21][22].…”

“…Like dexamethasone, these drugs are produced as inexpensive generics, are familiar to practicing physicians and are widely available in resource-poor countries. They have pleiotropic activities on inflammation, affect innate and adaptive immunity, and actively counteract endothelial dysfunction [3,4,[48][49][50][51][52]. Considered individually, these drugs are safe when given to patients with acute critical illness [53,54].…”

“…The pathogenesis of COVID-19 is characterized (among other things; see below) by endothelial dysfunction [2, 3]. Several inexpensive drugs like statins, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have immunometabolic activities that maintain or restore endothelial cell function [4].…”