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Virus-Cell Interactions

Lysosomal Proteases Are a Determinant of Coronavirus Tropism

Yuan Zheng, Jian Shang, Yang Yang, Chang Liu, Yushun Wan, Qibin Geng, Michelle Wang, Ralph Baric, Fang Li
Tom Gallagher, Editor
Yuan Zheng
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Jian Shang
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Yang Yang
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Chang Liu
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Yushun Wan
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Qibin Geng
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Michelle Wang
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Ralph Baric
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
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Fang Li
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, USA
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Tom Gallagher
Loyola University Medical Center
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DOI: 10.1128/JVI.01504-18
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ABSTRACT

Cell entry by coronaviruses involves two principal steps, receptor binding and membrane fusion; the latter requires activation by host proteases, particularly lysosomal proteases. Despite the importance of lysosomal proteases in both coronavirus entry and cell metabolism, the correlation between lysosomal proteases and cell tropism of coronaviruses has not been established. Here, we examined the roles of lysosomal proteases in activating coronavirus surface spike proteins for membrane fusion, using the spike proteins from severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) as the model system. To this end, we controlled the contributions from receptor binding and other host proteases, thereby attributing coronavirus entry solely or mainly to the efficiency of lysosomal proteases in activating coronavirus spike-mediated membrane fusion. Our results showed that lysosomal proteases from bat cells support coronavirus spike-mediated pseudovirus entry and cell-cell fusion more effectively than their counterparts from human cells. Moreover, purified lysosomal extracts from bat cells cleave cell surface-expressed coronavirus spikes more efficiently than their counterparts from human cells. Overall, our study suggests that different lysosomal protease activities from different host species and tissue cells are an important determinant of the species and tissue tropism of coronaviruses.

IMPORTANCE Coronaviruses are capable of colonizing new species, as evidenced by the recent emergence of SARS and MERS coronaviruses; they can also infect multiple tissues in the same species. Lysosomal proteases play critical roles in coronavirus entry by cleaving coronavirus surface spike proteins and activating the fusion of host and viral membranes; they also play critical roles in cell physiology by processing cellular products. How do different lysosomal protease activities from different cells impact coronavirus entry? Here, we controlled the contributions from known factors that function in coronavirus entry so that lysosomal protease activities became the only or the main determinant of coronavirus entry. Using pseudovirus entry, cell-cell fusion, and biochemical assays, we showed that lysosomal proteases from bat cells activate coronavirus spike-mediated membrane fusion more efficiently than their counterparts from human cells. Our study provides the first direct evidence supporting lysosomal proteases as a determinant of the species and tissue tropisms of coronaviruses.

  • Copyright © 2018 American Society for Microbiology.

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Lysosomal Proteases Are a Determinant of Coronavirus Tropism
Yuan Zheng, Jian Shang, Yang Yang, Chang Liu, Yushun Wan, Qibin Geng, Michelle Wang, Ralph Baric, Fang Li
Journal of Virology Nov 2018, 92 (24) e01504-18; DOI: 10.1128/JVI.01504-18

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Lysosomal Proteases Are a Determinant of Coronavirus Tropism
Yuan Zheng, Jian Shang, Yang Yang, Chang Liu, Yushun Wan, Qibin Geng, Michelle Wang, Ralph Baric, Fang Li
Journal of Virology Nov 2018, 92 (24) e01504-18; DOI: 10.1128/JVI.01504-18
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KEYWORDS

coronavirus spike protein
lysosomal proteases
species tropism
tissue tropism

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