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.
Highlights
As the human population expands, a closer proximity to wild animals and their habitat has resulted in a more frequent spillover of viral infections to humans and livestock
We have reviewed endothelial cell-virus interactions in emerging viral infections
We aimed to illustrate the diversity of such responses and identify common features that will bring us closer to understanding the role of endothelial cells in viral disease
Summary
As the human population expands, a closer proximity to wild animals and their habitat has resulted in a more frequent spillover of viral infections to humans and livestock. Viral antigens in blood and lymphatic endothelial cells of all examined tissues; Viral particles budding from the luminal side; Microvascular thrombosis; Multi-organ vascular involvement with widespread necrotic and haemorrhagic foci and oedema; Inflammation, except in per-acute disease. Such activation gives rise to a more sustained and efficient inflammatory response, but with the same consequences of increased blood flow, vascular leakage, and a coordinated leukocyte recruitment (Figure 1C) Both type I and type II activation of endothelial cells increase vascular permeability, at least in part by stimulating the formation of fibrillar adhesions to the extracellular matrix that destabilise endothelial adherens junctions and allow extravasation of plasma proteins [57]. For highly pathogenic and contagious agents, the proportion of deceased patients that undergo a full
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