Severe COVID-19: A multifaceted viral vasculopathy syndrome
| Autor: | Justin Mulvey, Sheridan Mikhail, Jeffrey Kubiak, David Suster, Jeffrey Laurence, Gerard J. Nuovo, Cynthia M. Magro, A. Neil Crowson |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine Pathology medicine.medical_specialty Complement Caspase 3 Spike protein In situ Pathology and Forensic Medicine 03 medical and health sciences Endothelialitis 0302 clinical medicine medicine Humans Vascular Diseases Interleukin 8 Lung Aged Aged 80 and over SARS-CoV-2 Thrombotic Microangiopathies business.industry Microangiopathy Virion COVID-19 Endothelial Cells Original Contribution General Medicine Middle Aged medicine.disease Complement system Endothelial stem cell 030104 developmental biology 030220 oncology & carcinogenesis Microvessels Spike Glycoprotein Coronavirus RNA Viral Capsid Proteins Female Tumor necrosis factor alpha Angiotensin-Converting Enzyme 2 Autopsy business Cytokine storm Viral load |
| Zdroj: | Annals of Diagnostic Pathology |
| ISSN: | 1092-9134 |
| DOI: | 10.1016/j.anndiagpath.2020.151645 |
| Popis: | The objective of this study was to elucidate the pathophysiology that underlies severe COVID-19 by assessing the histopathology and the in situ detection of infectious SARS-CoV-2 and viral capsid proteins along with the cellular target(s) and host response from twelve autopsies. There were three key findings: 1) high copy infectious virus was limited mostly to the alveolar macrophages and endothelial cells of the septal capillaries; 2) viral spike protein without viral RNA localized to ACE2+ endothelial cells in microvessels that were most abundant in the subcutaneous fat and brain; 3) although both infectious virus and docked viral spike protein was associated with complement activation, only the endocytosed pseudovirions induced a marked up-regulation of the key COVID-19 associated proteins IL6, TNF alpha, IL1 beta, p38, IL8, and caspase 3. Importantly, this microvasculitis was associated with characteristic findings on hematoxylin and eosin examination that included endothelial degeneration and resultant basement membrane zone disruption and reduplication. It is concluded that serious COVID-19 infection has two distinct mechanisms: 1) a microangiopathy of pulmonary capillaries associated with a high infectious viral load where endothelial cell death releases pseudovirions into the circulation, and 2) the pseudovirions dock on ACE2+ endothelial cells most prevalent in the skin/subcutaneous fat and brain that activates the complement pathway/coagulation cascade resulting in a systemic procoagulant state as well as the expression of cytokines that produce the cytokine storm. The data predicts a favorable response to therapies based on either removal of circulating viral proteins and/or blunting of the endothelial-induced response. Highlights • SARS-CoV-2 causes serious disease via two distinct mechanisms • One mechanism is damage to the alveolar wall (microangiopathy) associated with high viral copy numbers • The other mechanism is circulating viral capsid proteins that dock on ACE2+ endothelia • The ACE2+ endothelia are most prominent in the subcutaneous fat and brain • Endocytosis of viral capsid protein by endothelia induces cell death, cytokine expression, and complement activation (endothelialitis) |
| Databáze: | OpenAIRE |
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