Lack of Evidence of Angiotensin-Converting Enzyme 2 Expression and Replicative Infection by SARS-CoV-2 in Human Endothelial Cells

McCracken, Ian R.; Saginc, Gaye; He, Liqun; Huseynov, Alik; Daniels, Alison; Fletcher, Sarah; Peghaire, Claire; Kalna, Viktoria; Andaloussi-Mäe, Maarja; Muhl, Lars; Craig, Nicky; Griffiths, Samantha J.; Haas, Jürgen; Tait-Burkard, Christine; Lendahl, Urban; Birdsey, Graeme M.; Betsholtz, Christer; Noseda, Michela; Baker, Andrew H.; Randi, Anna M.

doi:10.1161/circulationaha.120.052824

Cited by 185 publications

(211 citation statements)

References 5 publications

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“…Endothelial injury following inflammatory damage, including the increasingly recognized pulmonary artery vasculitis (10,24) in COVID-19, may result in the initiation of a pro-coagulant process involving these cells (43). Alternatively, this endothelial injury could be triggered by direct viral infection of vascular cells (though this possibility is uncertain (43,44), viral replication in non-respiratory tissues is commonly observed at post-mortem (10, 13)); or thrombin mediated activation of IL-1α (40). This pro-coagulant role could lead to the deposition of microthrombi, evident in COVID-19 (10), activation of the clotting cascade and ultimately elevated D-dimer levels through the degradation of fibrin rich thrombi (34).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

et al. 2021

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While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

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Section: Discussionmentioning

confidence: 99%

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

et al. 2021

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“…This has led to the hypothesis that endotheliitis can induce immune reactions with thrombosis [30]. Although one study could not demonstrate SARS-CoV-2 invasion in human endothelial cells [31], it may be premature to reject this hypothesis.…”

Section: Multi-systemic Penetrance and Endotheliitis In Covid-19mentioning

confidence: 99%

COVID-19 and the clinical course of rheumatic manifestations

2021

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The manifestations of COVID-19 have been evolving over time. Various post-COVID-19 syndromes are being recognised. Various viruses have been implicated in the pathogenesis of autoimmune diseases, and we expect a similar outcome with the severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 virus penetrates various tissues and organs and has a predisposition to lead to endotheliitis that may cause vascular manifestations including thrombosis. SARS-CoV-2 has been shown to activate Toll-like receptors and the complement system. It perpetuates NETosis and leads to autoantibody formation. These predispose to systemic autoimmunity. Both reactive arthritis and connective tissue disorders such as lupus and inflammatory myositis have been reported after COVID-19. Other reported autoimmune disorders include haemolytic anaemia, immune thrombocytopenia, cutaneous vasculitis, and Guillain Barré-like acute demyelinating disorders. The multisystem inflammatory syndrome in children and its adult counterpart are another post-COVID-19 entity that presents as an admixture of Kawasaki disease and staphylococcal toxic shock syndrome. Patients with preexisting rheumatic diseases may flare during the SARS-CoV-2 infection. They may develop novel autoimmune features also. The immune-suppressants used during the acute COVID-19 illness may confound the outcomes whereas comorbidities present in patients with rheumatic diseases may mask them. There is an urgent need to follow-up patients recovering from COVID and monitor autoantibody production in the context of rheumatic manifestations. Key Points • COVID-19 is associated with both innate and acquired immune reactions and production of various autoantibodies. • Various immune-mediated manifestations such as arthritis, myositis, haemolytic anaemia, thrombocytopenia, and acute demyelination may develop after COVID-19. • Longitudinal cohort data are warranted to describe, predict, and test prevent various rheumatic manifestations in post-COVID-19 subjects.

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“…Using this method, expression of genes of interest can be demonstrated in specific cell types following cluster analysis of gene expression profiles 41 , 42 . By adopting this powerful new approach, several laboratories have now shown that ACE2 is not expressed in endothelial cells from mouse and human brain, heart, lungs and skin [43] , [44] , [45] , [46] or is expressed at low levels 47 , 48 . Epigenetic analysis of the human umbilical vein endothelial cells (HUVEC) chromatin landscape with genome-wide ChIP-seq data for histone modifications and DNase I hypersensitivity from ENCODE (Encyclopedia of DNA Elements) has corroborated the scRNA-Seq findings by revealing absence of activation marks and presence of repressive marks in the ACE2 locus 45 .…”

Section: Emerging New Evidence That the Sars-cov-2 Receptor Ace2 Is Not Expressed At Significant Levels In Endothelial Cellsmentioning

confidence: 99%

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

Nicosia

Ligresti

Caporarello

et al. 2021

The American Journal of Pathology

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COVID-19 patients who are critically ill develop vascular complications characterized by thrombosis of small, medium and large vessels. Dysfunction of the vascular endothelium due to the 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 ACE2 – 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. Here we review the vascular pathology of COVID-19 and critically discuss the potential mechanisms of endothelial injury in this disease.

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Lack of Evidence of Angiotensin-Converting Enzyme 2 Expression and Replicative Infection by SARS-CoV-2 in Human Endothelial Cells

Cited by 185 publications

References 5 publications

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

COVID-19 and the clinical course of rheumatic manifestations

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

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