Asialoglycoprotein receptor 1 promotes SARS-CoV-2 infection of human normal hepatocytes.

Publication date: Feb 14, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes multi-organ damage, which includes hepatic dysfunction, as observed in over 50% of COVID-19 patients. Angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into host cells, and studies have shown the presence of intracellular virus particles in human hepatocytes that express ACE2, but at extremely low levels. Consequently, we asked if hepatocytes might express receptors other than ACE2 capable of promoting the entry of SARS-CoV-2 into cells. To address this question, we performed a genome-wide CRISPR-Cas9 activation library screening and found that Asialoglycoprotein receptor 1 (ASGR1) promoted SARS-CoV-2 pseudovirus infection of HeLa cells. In Huh-7 cells, simultaneous knockout of ACE2 and ASGR1 prevented SARS-CoV-2 pseudovirus infection. In the immortalized THLE-2 hepatocyte cell line and primary hepatic parenchymal cells, both of which barely expressed ACE2, SARS-CoV-2 pseudovirus could successfully establish an infection. However, after treatment with ASGR1 antibody or siRNA targeting ASGR1, the infection rate significantly dropped, suggesting that SARS-CoV-2 pseudovirus infects hepatic parenchymal cells mainly through an ASGR1-dependent mechanism. We confirmed that ASGR1 could interact with Spike protein, which depends on receptor binding domain (RBD) and N-terminal domain (NTD). Finally, we also used Immunohistochemistry and electron microscopy to verify that SARS-CoV-2 could infect primary hepatic parenchymal cells. After inhibiting ASGR1 in primary hepatic parenchymal cells by siRNA, the infection efficiency of the live virus decreased significantly. Collectively, these findings indicate that ASGR1 is a candidate receptor for SARS-CoV-2 that promotes infection of hepatic parenchymal cells.

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Concepts Keywords
Asialoglycoprotein Ace2
Hepatic Asgr1
Library Asialoglycoprotein
Live Cells
Pseudovirus Cov


Type Source Name
disease MESH SARS-CoV-2 infection
pathway REACTOME SARS-CoV-2 Infection
disease VO Severe acute respiratory syndrome coronavirus 2
disease MESH causes
disease VO organ
disease IDO entry into host
disease MESH infection
disease IDO cell
disease VO efficiency
drug DRUGBANK Angiotensin II
disease IDO host
disease MESH viral infection
disease IDO replication
disease MESH Infectious Diseases
drug DRUGBANK Coenzyme M
drug DRUGBANK Ademetionine
drug DRUGBANK Methylphenidate
disease VO Lentivirus
drug DRUGBANK Puromycin
disease IDO process
disease IDO blood
disease MESH tumor
disease VO effective
pathway KEGG Endocytosis
drug DRUGBANK Proline
disease VO Viruses
disease MESH alcoholic fatty liver
disease MESH non alcoholic fatty liver disease
disease MESH liver diseases
drug DRUGBANK Ursodeoxycholic acid
pathway KEGG Apoptosis
disease MESH inflammation
disease MESH cholestasis
drug DRUGBANK Serine
disease MESH liver cancer
disease VO USA
drug DRUGBANK Streptomycin
drug DRUGBANK Human Serum Albumin
disease IDO production
drug DRUGBANK Amino acids
disease VO storage
disease IDO assay
drug DRUGBANK Phosphate ion
drug DRUGBANK Sodium lauryl sulfate
disease MESH pneumonia
disease IDO infectivity
disease MESH complications
disease VO Venezuelan equine encephalitis virus
disease IDO intervention
disease MESH hepatocellular carcinoma
pathway KEGG Hepatocellular carcinoma
drug DRUGBANK (S)-Des-Me-Ampa
drug DRUGBANK Coenzyme A
disease VO vaccine

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