Endothelial cell infection and dysfunction, immune activation in severe COVID-19

Abstract

Rationale: Pulmonary vascular endotheliitis, perivascular inflammation, and immune activation are observed in COVID-19 patients. While the initial SARS-CoV-2 infection mainly infects lung epithelial cells, whether it also infects endothelial cells (ECs) and to what extent SARS-CoV-2-mediated pulmonary vascular endotheliitis is associated with immune activation remain to be determined. Methods: To address these questions, we studied SARS-CoV-2-infected K18-hACE2 (K18) mice, a severe COVID-19 mouse model, as well as lung samples from SARS-CoV-2-infected nonhuman primates (NHP) and patient deceased from COVID-19. We used immunostaining, RNAscope, and electron microscopy to analyze the organs collected from animals and patient. We conducted bulk and single cell (sc) RNA-seq analyses, and cytokine profiling of lungs or serum of the severe COVID-19 mice. Results: We show that SARS-CoV-2-infected K18 mice develop severe COVID-19, including progressive body weight loss and fatality at 7 days, severe lung interstitial inflammation, edema, hemorrhage, perivascular inflammation, systemic lymphocytopenia, and eosinopenia. Body weight loss in K18 mice correlated with the severity of pneumonia, but not with brain infection. We also observed endothelial activation and dysfunction in pulmonary vessels evidenced by the up-regulation of VCAM1 and ICAM1 and the downregulation of VE-cadherin. We detected SARS-CoV-2 in capillary ECs, activation and adhesion of platelets and immune cells to the vascular wall of the alveolar septa, and increased complement deposition in the lungs, in both COVID-19-murine and NHP models. We also revealed that pathways of coagulation, complement, K-ras signaling, and genes of ICAM1 and VCAM1 related to EC dysfunction and injury were upregulated, and were associated with massive immune activation in the lung and circulation.

SARS-CoV-2 infection of the pancreas promotes thrombofibrosis and is associated with new-onset diabetes

“…Evidence also suggests that SARS-CoV-2 infects endothelial cells and that COVID-19 is an endothelial cell disease ( 14 , 33 ). In severe cases, massive endothelial dysfunction, disseminated coagulopathy, and complement-induced thrombosis produce systemic microangiopathy and thromboembolism ( 34 ).…”

Role of SARS-CoV-2 -induced cytokines and growth factors in coagulopathy and thromboembolism

“…It suggests that these cells are susceptible to virus infection and contribute to inflammation either directly or indirectly via inflammatory mediators released by other cells such as epithelial and immune cells [61] . Similar to epithelial cells, endothelial cell function is significantly affected by SARS-CoV-2 in multiple ways [62] , [63] . Some of the major endothelial dysfunction involves reduced endothelium-dependent vasodilation leading to proinflammatory, procoagulant and hyperproliferation [64] , [65] .…”

Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19

“…Platelet activation in the setting of COVID-19 has been a topic of intense scientific research with several mechanisms being described. ACE2-dependent endothelial cell infection by SARS-CoV-2 has been documented early in the course of the pandemic [126] and confirmed in a recent experimental animal study of Qin et al [127]. COVID-19 cytokine storm-induced endotheliitis is also responsible for the impaired balance of anti-thrombotic substances such as NO and PGI 2 due to the reduced levels of arginine and the upregulation of asymmetric dimethylarginine, ultimately leading to a greater degree of platelet activation [128].…”