The two main findings of this study were: 1) human COVID-19 cases show diffuse pauci-inflammatory microvessel endothelial damage in the brain and other organs including the skin [[6], [7], [8]] from the endocytosis of circulating viral spike protein that induces C5b-9, caspase-3 and cytokine production that is associated with a microencephalopathy. This encephalopathy is marked, in part, by neuronal dysfunction, evidenced by increased nNOS and NMDAR2 plus the reduction of key neuronal proteins that include MFSD2a and SHIP1. 2) Injection of the S1 full length spike subunit into the tail vein of mice, but not the S2 subunit or truncated S1 subunit, induces an equivalent microvascular encephalopathy that shares with the human COVID-19 brain disease the endocytosis of the S1 subunit in ACE2+ endothelia, caspase 3, C5b-9, TNFα, and IL6 activation, and the over-expression of nNOS and much reduced expression of MFSD2a. The much milder clinical effects of the truncated S1 subunit suggests that the N-terminal region plays a role in spike S1-induced CNS injury.
In sum, the data presented indicates that the full-length S1 subunit of the spike protein of SARS-CoV-2 alone is capable, without the infectious virus, of inducing systemic microendothelial cell damage in mice with a cognate pattern of complement activation and increased cytokine expression and the concomitant thromboses/hypercoagulable state. This disease pattern strongly parallels the extra-pulmonary manifestations of severe human COVID-19 and suggests that the latter may not represent systemic infectious virus. Thus, prevention of the CNS disease so common in severe COVID-19 may require neutralization/removal of the circulating pseudovirions. The key point for the diagnostic anatomic pathologist is to focus their studies in patients with SARS-CoV-2 infection on degeneration of ACE2+ endothelia using routine H&E stains in conjunction with immunohistochemistry for ACE2, caspase 3 and, when possible, the spike protein.
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