Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?

Huertas, Alice; Montani, David; Savale, Laurent; Pichon, Jérémie; Tu, Ly; Parent, Florence; Guignabert, Christophe; Humbert, Marc

doi:10.1183/13993003.01634-2020

Cited by 334 publications

(357 citation statements)

References 52 publications

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“…Notably, SARS-CoV-2 has not been found to enter red blood cells 42 . However, the possibility that BSG could act as an accessory binding receptor for the virus has been speculated in several publications to possibly explain in part the link between SARS-CoV-2 infection and hematological symptoms in patients 38,39,43,44 . Our data suggest this hypothesis should be treated cautiously.…”

Section: Discussionmentioning

confidence: 99%

No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

Shilts

Wright

2020

Preprint

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The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses of the role of this host receptor in viral infection and pathogenesis. We sought to independently characterize the basigin-spike protein interaction. After conducting several lines of experiments, we report that we are unable to find evidence supporting the role of basigin as a putative spike-binding receptor. Recombinant forms of both the entire ectodomain and S1 domain of the SARS-CoV-2 spike protein that directly bind ACE2 do not interact with basigin expressed on the surface of human cells. Using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for direct binding of the viral spike to either of the two common isoforms of basigin. Given the pressing need for clarity on which targets of SARS-CoV-2 may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.

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Section: Discussionmentioning

confidence: 99%

No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

Shilts

Wright

2020

Preprint

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“…Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) infection, or Corona Virus Infectious Disease 2019 (COVID-19), may be complicated by the acute respiratory distress syndrome (ARDS) with reported high mortality rates between 26% and 61% (1,2). There are data suggesting that COVID-19 ARDS differs from "typical" ARDS by several aspects, including preserved respiratory system compliance (3), good tolerance to hypoxemia ("happy hypoxemia") (4), and prominent micro and macrovascular thrombotic changes in relation with extensive endothelial injury (5,6). On the cardiac side, COVID-19 has also been associated with myocardial injury (7), and altered right ventricle (RV) strain as an independent predictor of poor prognosis (8).…”

Section: Introductionmentioning

confidence: 99%

Right Ventricular-Arterial Uncoupling Independently Predicts Survival in COVID-19 ARDS

D′Alto

Marra

Severino

et al. 2020

Preprint

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Aim. To investigate the prevalence and prognostic impact of right heart failure and right ventricular-arterial uncoupling in Corona Virus Infectious Disease 2019 (COVID-19) complicated by an acute respiratory distress syndrome (ARDS).Methods. Ninety-four consecutive patients (mean age 64 yrs) admitted for acute respiratory failure on COVID-19 were enrolled. Coupling of right ventricular function to the pulmonary circulation was evaluated by a comprehensive trans-thoracic echocardiography with focus on the tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (PASP) ratio Results. The majority of patients needed ventilatory support, which was non-invasive in 22 and invasive in 37. There were 25 deaths, all in the invasively ventilated patients. Survivors were younger (62±13 vs 68±12 years, p=0.033), less often overweight or usual smokers, had lower NT-proBNP and interleukin-6, and higher arterial partial pressure of oxygen (PaO2)/fraction of inspired O2 (FIO2) ratio (270±104 vs 117±57 mmHg, p<0.001). In the non-survivors, PASP was increased (42±12 vs 30±7 mmHg, p<0.001), while TAPSE was decreased (19±4 vs 25±4 mm, p<0.001). Accordingly the TAPSE/PASP ratio was lower than in the survivors (0.51±0.22 vs 0.89±0.29 mm/mmHg, p<0.001). At univariate/multivariable analysis, the TAPSE/PASP (HR:0.026; 95%CI:0.01-0.579; p:0.019) and PaO2/FIO2 (HR:0.988; 95%CI:0.988-0.998; p:0.018) ratios were the only independent predictors of mortality, with ROC-determined cut-off values of 159 mmHg and 0.635 mm/mmHg respectively.Conclusions. COVID-19 ARDS is associated with clinically relevant uncoupling of right ventricular function from the pulmonary circulation; bedside echocardiography of TAPSE/PASP adds to the prognostic relevance of PaO2/FIO2 in ARDS on COVID-19.

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“…Although the mechanism is not clear the increased proinflammatory cytokine release might cause an endothelial dysfunction. In addition to the origin of endothelial cells from different organs, comorbidities like obesity and diabetes might render endothelial cells susceptible to be infected as recently described (Huertas et al, 2020;Pons et al, 2020).…”

Section: Sars-cov-2 Infects Epithelial Cells Within the Alveolus-on-amentioning

confidence: 99%

SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction

Deinhardt‐Emmer

Böttcher

Haring

et al. 2020

Preprint

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Infections with SARS-CoV-2 lead to mild to severe coronavirus disease-19 (COVID-19) with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses.To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human alveolus-on-a-chip model composed of epithelial, endothelial, and mononuclear cells.Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including the interferon expression. By contrast, the adjacent endothelial layer was no infected and did neither show productive virus replication or interferon release. With prolonged infection, both cell types are damaged, and the barrier function is deteriorated, allowing the viral particles to overbear.In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokine release, which results in the damage of the alveolar barrier function and viral dissemination.

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Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?

Abstract: Endothelial cell dysfunction and impaired microcirculatory function contribute markedly to lifethreatening complications of COVID-19, such as venous thromboembolic disease and multiple organ involvement https://bit.ly/3cZMjKV

Cited by 334 publications

References 52 publications

No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

Right Ventricular-Arterial Uncoupling Independently Predicts Survival in COVID-19 ARDS

SARS-CoV-2 causes severe alveolar inflammation and barrier dysfunction

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