Christer Betsholtz, Ph.D.
Professor and Head
Department of Immunology, Genetics and Pathology
June 10, 2020 at 1:00pm EST
Christer Betsholtz -
Christer Betsholtz is currently Professor of Vascular and Tumor Biology at Uppsala University and jointly active as Professor of Vascular Biology and Director for the Integrated Cardio-Metabolic Centre at Department of Medicine, Karolinska Institutet, Huddinge, Sweden. He graduated from Uppsala University in 1986 and held junior faculty positions there between 1986 and 1993. He was Professor of Medical Biochemistry at Göteborg University, Sweden, 1993-2004. He is member of the European Molecular Biology Organization (EMBO), Academia Europaea, the Royal Swedish Academy of Sciences, and the Nobel Assembly. His research is focused on growth factors and their roles in angiogenesis and vascular maturation and specialization. A particular interest is microvascular pericytes and their roles in health and disease.
Covid19 patients with severe disease, and especially those in intensive care, experience a “second wave” of mysterious symptoms including hypercoagulation, widespread thrombosis and systemic inflammation (“cytokine storm”). These clinical observations suggest a vascular culprit for the Covid-19 disease that goes beyond the problems with deep vein thromboses in immobilized patients.
We have found that the SARS-CoV-2 virus receptor ACE2 is highly and specifically expressed on pericytes, but importantly not on endothelial cells or other vascular and perivascular cell types. We also find that impairment of pericyte function leads to a strong pro-thrombotic response in neighboring endothelial cells.
These findings have two important and immediately relevant implications: First, they provide a plausible explanation for the risk factor/co-morbidity profile of severe Covid-19 disease, as only in the instance of an impaired endothelial barrier function, as observed systemically in diabetes and hypertension, and locally in ischemic heart and brain diseases, the virus would escape the blood and infect pericytes (and other putative non-surface epithelial ACE2 positive cell types). Second, SARS-CoV-2 infection of pericytes may impair their function leading to pro-thrombotic and pro-inflammatory responses in the endothelium. We provide supporting evidence for this scenario by showing that pericyte loss causes a remarkable up-regulation of expression and secretion of Von Willebrand Factor from the neighboring endothelial cells, intravascular platelet aggregation and fibrin deposition. Immune attack on infected pericytes may furthermore elicit inflammatory responses that further enhance vascular permeability, virus extravasation, pericyte infection and more inflammation, in a vicious circle.
These findings may have immediate clinical relevance in spurring further discussion about the most suitable anti-coagulant therapy to counter a microvessel-initiated coagulopathy. It should also spur discussions about the best ways forward to target virus dissemination through the blood. A pre-print version of a manuscript describing these findings has been posted at: https://biorxiv.org/cgi/content/short/2020.05.11.088500v1.
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