A cohort autopsy study defines COVID-19 systemic pathogenesis

Abstract

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood–air barrier, blood–testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Activation of Tenofovir Alafenamide and Sofosbuvir in the Human Lung and Its Implications in the Development of Nucleoside/Nucleotide Prodrugs for Treating SARS-CoV-2 Pulmonary Infection

“…Unlike CatA, which is expressed in a broad range of tissues [16,30], CES1 is predominantly expressed in the liver [16,31]. In the context of COVID-19, human respiratory systems, including the airway and lung tissues, are the major infection sites [32], and thus are the most important target activating sites for antiviral prodrugs. It is noteworthy that, in human airway epithelial cells, the expression of CES1 was very low, while CatA expression was about 2-fold higher than CES1 [13,27].…”

Inflammasome activation at the crux of severe COVID-19

“… 118 ). SARS-CoV-2 E protein functions as a K + -permeable cation channel, which lyses cells when overexpressed and induces ARDS-like pathology in mice 119 . Beyond these mechanisms, it is conceivable that SARS-CoV-2 activates inflammasomes by novel processes not known to occur by SARS-CoV.…”

“…Lysis of infected lung cells could secrete alarmins to activate inflammatory macrophages and promote their recruitment to the lung 128 . Supernatants from Vero E6 cells lysed by overexpression of SARS-CoV-2 E protein can induce IL-1β secretion by recipient macrophages 119 , likely through NLRP3, but also possibly other inflammasome sensors, such as AIM2 and NLRC4 (ref. 58 ).…”

Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland

“…Taken into account the high number of deaths resulting from the disease worldwide (>3,404,000 until 19 May 2021) [2], documentation of the histological lesions is still relatively limited, with a disproportionately low number of autopsy studies. Diffuse alveolar damage (DAD), the histomorphological correlate of ARDS, has been most frequently reported, as have been thromboembolic events [3][4][5][6][7][8][9][10][11][12][13].…”