Abstract
Hepatic disease is common in severe COVID-19. This study compared the histologic/molecular findings in the liver in fatal COVID-19 (n = 9) and age-matched normal controls (n = 9); three of the fatal COVID-19 livers had pre-existing alcohol use disorder (AUD). Controls showed a high resident population of sinusoidal macrophages that had variable ACE2 expression. Histologic findings in the cases included periportal/lobular inflammation. SARS-CoV2 RNA and nucleocapsid protein were detected in situ in 2/9 COVID-19 livers in low amounts. In 9/9 cases, there was ample in situ SARS-CoV-2 spike protein that co-localized with viral matrix and envelope proteins. The number of cells positive for spike/100× field was significantly greater in the AUD/COVID-19 cases (mean 5.9) versus the non-AUD/COVID-19 cases (mean 0.4, p < 0.001) which was corroborated by Western blots. ACE2+ cells were 10× greater in AUD/COVID-19 livers versus the other COVID-19/control liver samples (p < 0.001). Co-expression experiments showed that the spike protein localized to the ACE2 positive macrophages and, in the AUD cases, hepatic stellate cells that were activated as evidenced by IL6 and TNFα expression. Injection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated macrophages. It is concluded that endocytosed viral spike protein can induce hepatitis in fatal COVID-19. This spike induced hepatitis is more robust in the livers with pre-existing AUD which may relate to why patients with alcohol abuse are at higher risk of severe liver disease with SARS-CoV2 infection.
Keywords: Alcohol liver disease; COVID-19; Hepatic stellate cells; Liver; Spike protein.
【저자키워드】 COVID-19, Spike protein, liver, Alcohol liver disease, Hepatic stellate cells, 【초록키워드】 Inflammation, Macrophage, ACE2, SARS-CoV2, macrophages, severe COVID-19, spike, IL6, alcohol, SARS-CoV2 infection, Spike protein, nucleocapsid protein, RNA, Protein, Viral, Hepatitis, mice, SARS-CoV-2 spike protein, Patient, Control, experiment, ACE2 expression, disease, expression, liver, Liver disease, Alcohol Abuse, viral spike protein, western blots, higher risk, subunit, injection, severe liver disease, TNFα, disorder, fatal COVID-19, positive, activated macrophages, lobular inflammation, envelope proteins, hepatic disease, histologic findings, hepatic, Cell, livers, robust, greater, significantly, activated, the spike protein, induce, evidenced, endocytosed, hepatic stellate cell, 【제목키워드】 molecular, disorder, histologic,