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SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems.
J Med Virol. 2021 12; 93(12):6671-6685.JM

Abstract

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of syndromes involving multiple organ systems and is primarily mediated by viral spike (S) glycoprotein through the receptor-binding domain (RBD) and numerous cellular proteins including ACE2, transmembrane serine protease 2 (TMPRSS2), kidney injury molecule-1 (Kim-1), and neuropilin-1 (NRP-1). In this study, we examined the entry tropism of SARS-CoV-2 and SARS-CoV using S protein-based pseudoviruses to infect 22 cell lines and 3 types of primary cells isolated from respiratory, urinary, digestive, reproductive, and immune systems. At least one cell line or type of primary cell from each organ system was infected by both pseudoviruses. Infection by pseudoviruses is effectively blocked by S1, RBD, and ACE2 recombinant proteins, and more weakly by Kim-1 and NRP-1 recombinant proteins. Furthermore, cells with robust SARS-CoV-2 pseudovirus infection had strong expression of either ACE2 or Kim-1 and NRP-1 proteins. ACE2 glycosylation appeared to be critical for the infections of both viruses as there was a positive correlation between infectivity of either SARS-CoV-2 or SARS-CoV pseudovirus with the level of glycosylated ACE2 (gly-ACE2). These results reveal that SARS-CoV-2 cell entry could be mediated by either an ACE2-dependent or -independent mechanism, thus providing a likely molecular basis for its broad tropism for a wide variety of cell types.

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Authors+Show Affiliations

Zhang F
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Li W
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Feng J
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Ramos da Silva S
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Ju E
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Zhang H
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Chang Y
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Moore PS
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Guo H
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Gao SJ
Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

MeSH

Angiotensin-Converting Enzyme 2Blotting, WesternCOVID-19Cell LineCells, CulturedFluorescent Antibody TechniqueGastrointestinal TractGenitaliaHepatitis A Virus Cellular Receptor 1HumansImmune SystemNeuropilin-1Respiratory SystemSARS-CoV-2Serine EndopeptidasesVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34324210

Citation

Zhang, Fei, et al. "SARS-CoV-2 Pseudovirus Infectivity and Expression of Viral Entry-related Factors ACE2, TMPRSS2, Kim-1, and NRP-1 in Human Cells From the Respiratory, Urinary, Digestive, Reproductive, and Immune Systems." Journal of Medical Virology, vol. 93, no. 12, 2021, pp. 6671-6685.
Zhang F, Li W, Feng J, et al. SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems. J Med Virol. 2021;93(12):6671-6685.
Zhang, F., Li, W., Feng, J., Ramos da Silva, S., Ju, E., Zhang, H., Chang, Y., Moore, P. S., Guo, H., & Gao, S. J. (2021). SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems. Journal of Medical Virology, 93(12), 6671-6685. https://doi.org/10.1002/jmv.27244
Zhang F, et al. SARS-CoV-2 Pseudovirus Infectivity and Expression of Viral Entry-related Factors ACE2, TMPRSS2, Kim-1, and NRP-1 in Human Cells From the Respiratory, Urinary, Digestive, Reproductive, and Immune Systems. J Med Virol. 2021;93(12):6671-6685. PubMed PMID: 34324210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 pseudovirus infectivity and expression of viral entry-related factors ACE2, TMPRSS2, Kim-1, and NRP-1 in human cells from the respiratory, urinary, digestive, reproductive, and immune systems. AU - Zhang,Fei, AU - Li,Wan, AU - Feng,Jian, AU - Ramos da Silva,Suzane, AU - Ju,Enguo, AU - Zhang,Hu, AU - Chang,Yuan, AU - Moore,Patrick S, AU - Guo,Haitao, AU - Gao,Shou-Jiang, Y1 - 2021/08/04/ PY - 2021/07/24/revised PY - 2021/06/21/received PY - 2021/07/27/accepted PY - 2021/7/30/pubmed PY - 2021/10/28/medline PY - 2021/7/29/entrez KW - Angiotensin-converting enzyme 2 (ACE2) KW - Kim-1 KW - NRP-1 KW - SARS-CoV KW - SARS-CoV-2 KW - TMPRSS2 KW - and glycosylation KW - pseudovirus KW - receptor binding domain (RBD) KW - spike protein KW - viral entry tropism KW - virus receptor SP - 6671 EP - 6685 JF - Journal of medical virology JO - J Med Virol VL - 93 IS - 12 N2 - Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of syndromes involving multiple organ systems and is primarily mediated by viral spike (S) glycoprotein through the receptor-binding domain (RBD) and numerous cellular proteins including ACE2, transmembrane serine protease 2 (TMPRSS2), kidney injury molecule-1 (Kim-1), and neuropilin-1 (NRP-1). In this study, we examined the entry tropism of SARS-CoV-2 and SARS-CoV using S protein-based pseudoviruses to infect 22 cell lines and 3 types of primary cells isolated from respiratory, urinary, digestive, reproductive, and immune systems. At least one cell line or type of primary cell from each organ system was infected by both pseudoviruses. Infection by pseudoviruses is effectively blocked by S1, RBD, and ACE2 recombinant proteins, and more weakly by Kim-1 and NRP-1 recombinant proteins. Furthermore, cells with robust SARS-CoV-2 pseudovirus infection had strong expression of either ACE2 or Kim-1 and NRP-1 proteins. ACE2 glycosylation appeared to be critical for the infections of both viruses as there was a positive correlation between infectivity of either SARS-CoV-2 or SARS-CoV pseudovirus with the level of glycosylated ACE2 (gly-ACE2). These results reveal that SARS-CoV-2 cell entry could be mediated by either an ACE2-dependent or -independent mechanism, thus providing a likely molecular basis for its broad tropism for a wide variety of cell types. SN - 1096-9071 UR - https://www.unboundmedicine.com/medline/citation/34324210/SARS_CoV_2_pseudovirus_infectivity_and_expression_of_viral_entry_related_factors_ACE2_TMPRSS2_Kim_1_and_NRP_1_in_human_cells_from_the_respiratory_urinary_digestive_reproductive_and_immune_systems_ DB - PRIME DP - Unbound Medicine ER -