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Review
. 2021 Feb 24:8:619690.
doi: 10.3389/fcvm.2021.619690. eCollection 2021.

Endothelial Cells in Emerging Viral Infections

Johanna Hol Fosse  1 , Guttorm Haraldsen  2   3 , Knut Falk  1   4 , Reidunn Edelmann  5
Affiliations
Review

Endothelial Cells in Emerging Viral Infections

Johanna Hol Fosse et al. Front Cardiovasc Med. .

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.

Keywords: SARS-CoV-2; emerging infections; endothelium; inflammation; vascular dysfunction and damage; virus.

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Conflict of interest statement

KF was employed by the company AquaMed Consulting AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Endothelial function in homeostasis and viral infection. (A,B) In homeostasis, endothelial cells promote a non-adherent vascular surface that promotes tissue perfusion, limits inflammation and the transvascular movement of cells and proteins, and prevents clotting. (A,C) Upon viral infection or tissue damage, endothelial cells are activated directly by viral components or indirectly by soluble mediators (IL-1, TNF, IL-6, IFNa, IFNb). Such activation initiates signalling that culminates in activation and nuclear translocation of IRF and NF-kB transcription factors. This results in expression of interferon-stimulated genes (ISGs) and inflammatory mediators (e.g., tissue factor, selectins, chemokines, and adhesion molecules) that promote antiviral responses, clotting, vascular permeability, and leukocyte recruitment. In addition, type I activation of endothelial cells, for example by thrombin, causes a rapid release of pre-synthesised molecules (e.g., VWF, ANGPT2, P-selectin, and CXCL8) with similar effects. (A,D) In the case of overwhelming or persistent activation, endothelial cells may become dysfunctional, resulting in loss of control of vascular tone, permeability, and coagulation. In addition, direct viral damage to the endothelium further disrupts the vascular barrier and exposes pro-thrombotic factors (tissue factor, collagen) that exacerbate dysfunctional coagulation.
Figure 2
Figure 2
Host factors that regulate viral entry into endothelial cells. (A) After replication in mucosal epithelial cells (EPC), viruses can infect endothelial cells (EC) abluminally or gain access to the luminal surface by transcytosis, paracellular dissemination through activated endothelial junctions, or by being carried by cells that traffic between blood and tissues, like monocyte/macrophages (Mø). (B) Viruses attach to carbohydrate or protein molecules on the endothelial cell surface. Typically, attachment to protein receptors and sialic acid variants is highly specific, while attachment to heparan sulphates and scavenger receptors is more promiscuous. (C) The viral fusion protein is primed, typically by proteolytic cleavage, in the Golgi during biosynthesis, on the cell surface, or in endosomes, depending on protease susceptibility. (D) Further activation of the viral fusion peptide and viral cytoplasmic delivery may happen on the cell surface or in endosomes and depends on a conformational change triggered by receptor binding and/or specific pH requirements. Some viruses only fuse with host membranes of specific compositions.
Figure 3
Figure 3
Functional regulation of vascular permeability in viral disease. The vascular barrier integrity is controlled by two main components: the glycocalyx (GC) and the endothelial adherens junctions (EAJs). (A) In the resting state, several signalling pathways promote VE-cadherin-supported junctional integrity. In addition to maintaining an intact vascular barrier, VE-cadherin-signalling also skews VEGFR2-signalling toward eNOS-activation and survival-promoting pathways. (B) Upon type I (thrombin) and/or type II (IL-1, TNF) activation, the cytoskeleton is reorganised, and fibrillar adhesions are formed in an ANGPT2-dependent manner. Furthermore, activation by cytokines or flaviviral NS1 stimulates endothelial production of enzymes that mediate glycocalyx-shedding and further disrupts the vascular barrier. Hantavirus surface proteins bind and inactivate the EAJ-supportive action of β3-integrins, thereby increasing VEGF-stimulated permeability. In addition, hantavirus N protein promotes RhoA-signalling and increases permeability independent of VEGF-signalling.
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References

    1. R&D blueprints. Key Actions by Disease. Oslo: World Health Organisation; (2020).
    1. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. . Endothelial cell infection and endotheliitis in COVID-19. Lancet. (2020) 395:1417–8. 10.1016/S0140-6736(20)30937-5 - DOI - PMC - PubMed
    1. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. . Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. (2020) 383:120–8. 10.1056/NEJMoa2015432 - DOI - PMC - PubMed
    1. Colmenero I, Santonja C, Alonso-Riano M, Noguera-Morel L, Hernandez-Martin A, Andina D, et al. . SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. (2020) 183:729–37. 10.1111/bjd.19327 - DOI - PMC - PubMed
    1. Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, et al. . Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. (2020) 181:905–13 e7. 10.1016/j.cell.2020.04.004 - DOI - PMC - PubMed

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