Docked SARS CoV-2 Proteins within the Cutaneous and Subcutaneous Microvasculature and their Role in the Pathogenesis of Severe COVID-19

The purpose of this study was to examine the deltoid skin biopsy in twenty-three COVID-19 patients, most severely ill, for vascular complement deposition and correlate this with SARS CoV-2 viral RNA and protein localization and ACE2 expression The deltoid skin microvascular complement screen has been applied to patients with various systemic complement-mediated microvascular syndromes best exemplified by atypical hemolytic uremic syndrome In 21/23 cases, substantial microvascular deposition of complement components was identified The two patients without significant complement deposition included one patient with moderate disease and a severely ill patient who although on a ventilator for a day was discharged after 3 days The dominant microvascular complement immunoreactant identified was the terminal membranolytic attack complex C5b-9 Microvascular complement deposition strongly co-localized in situ with the SARS CoV-2 viral proteins including spike glycoproteins in the endothelial cells as well as the viral receptor ACE2 in lesional and non-lesional skin;viral RNA was not evident Microvascular SARS CoV-2 viral protein, complement and ACE2 expression was most conspicuous in the subcutaneous fat Although the samples from severely ill patients with COVID-19 were from grossly normal skin, light microscopically focal microvascular abnormalities were evident that included endothelial cell denudement, basement membrane zone reduplication and small thrombi It is concluded that complement activation is common in grossly normal skin, primarily in the subcutaneous fat which may provide a link between severe disease and obesity, in people with severe COVID-19 and the strong co-localization with the ACE2 receptor and viral capsid proteins without viral RNA suggests that circulating viral proteins (i e pseudovirions) may dock onto the endothelial of these microvessels and induce complement activation