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The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection.

ABSTRACT: In severe SARS-CoV-2 infections, emerging data including recent histopathological studies have emphasized the crucial role of endothelial cells (ECs) in vascular dysfunction, immunothrombosis, and inflammation.Histopathological studies have evidenced direct viral infection of ECs, endotheliitis with diffuse endothelial inflammation, and micro- and macrovascular thrombosis both in the venous and arterial circulations. Venous thrombotic events, particularly pulmonary embolism, with elevated D-dimer and coagulation activation are highly prevalent in COVID-19 patients. The pro-inflammatory cytokine storm, with elevated levels of interleukin-6 (IL-6), IL-2 receptor, and tumor necrosis factor-α, could also participate in endothelial dysfunction and leukocyte recruitment in the microvasculature. COVID-19-induced endotheliitis may explain the systemic impaired microcirculatory function in different organs in COVID-19 patients. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS-2) blockade, coagulation activation, and immunomodulatory therapies, such as anti-IL-6 strategies. Studies focusing on endothelial dysfunction in COVID-19 patients are warranted as to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.

SUBMITTER: Pons S

PROVIDER: S-EPMC7296907 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Infections with SARS-CoV-2 can be asymptomatic, but they can also be accompanied by a variety of symptoms that result in mild to severe coronavirus disease-19 (COVID-19) and are sometimes associated 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 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 interferon expression. By contrast, the adjacent endothelial layer was neither infected nor did it show productive virus replication or interferon release. With prolonged infection, both cell types were damaged, and the barrier function was 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 cytokines or components induced during infection, which further results in the damage of the epithelial/endothelial barrier function and viral dissemination.IMPORTANCESARS-CoV-2 challenges healthcare systems and societies worldwide in unprecedented ways. Although numerous new studies have been conducted, research to better understand the molecular pathogen-host interactions are urgently needed. For this, experimental models have to be developed and adapted. In the present study we used mono cell-culture systems and we established a complex chip model, where epithelial and endothelial cells are cultured in close proximity. We demonstrate that epithelial cells can be infected with SARS-CoV-2, while the endothelium did not show any infection signs. Since SARS-CoV-2 is able to establish viremia, the link to thromboembolic events in severe COVID-19 courses is evident. However, whether the endothelial layer is damaged by the viral pathogens or whether other endothelial-independent homeostatic factors are induced by the virus is essential for understanding the disease development. Therefore, our study is important as it demonstrates that the endothelial layer could not be infected by SARS-CoV-2 in our in vitro experiments, but we were able to show the destruction of the epithelial-endothelial barrier in our chip model. From our experiments we can assume that virus-induced host factors disturbed the epithelial-endothelial barrier function and thereby promote viral spread.

Project description:Background and Objectives: The severe forms of SARS-CoV-2 pneumonia are associated with acute hypoxic respiratory failure and high mortality rates, raising significant challenges for the medical community. The objective of this paper is to present the importance of early quantitative evaluation of radiological changes in SARS-CoV-2 pneumonia, including an alternative way to evaluate lung involvement using normal density clusters. Based on these elements we have developed a more accurate new predictive score which includes quantitative radiological parameters. The current evolution models used in the evaluation of severe cases of COVID-19 only include qualitative or semi-quantitative evaluations of pulmonary lesions which lead to a less accurate prognosis and assessment of pulmonary involvement. Materials and Methods: We performed a retrospective observational cohort study that included 100 adult patients admitted with confirmed severe COVID-19. The patients were divided into two groups: group A (76 survivors) and group B (24 non-survivors). All patients were evaluated by CT scan upon admission in to the hospital. Results: We found a low percentage of normal lung densities, PaO2/FiO2 ratio, lymphocytes, platelets, hemoglobin and serum albumin associated with higher mortality; a high percentage of interstitial lesions, oxygen flow, FiO2, Neutrophils/lymphocytes ratio, lactate dehydrogenase, creatine kinase MB, myoglobin, and serum creatinine were also associated with higher mortality. The most accurate regression model included the predictors of age, lymphocytes, PaO2/FiO2 ratio, percent of lung involvement, lactate dehydrogenase, serum albumin, D-dimers, oxygen flow, and myoglobin. Based on these parameters we developed a new score (COV-Score). Conclusions: Quantitative assessment of lung lesions improves the prediction algorithms compared to the semi-quantitative parameters. The cluster evaluation algorithm increases the non-survivor and overall prediction accuracy.COV-Score represents a viable alternative to current prediction scores, demonstrating improved sensitivity and specificity in predicting mortality at the time of admission.

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The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection.

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