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      Distinct spatial arrangements of ACE2 and TMPRSS2 expression in Syrian hamster lung lobes dictates SARS-CoV-2 infection patterns

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          Abstract

          SARS-CoV-2 attaches to angiotensin-converting enzyme 2 (ACE2) to gain entry into cells after which the spike protein is cleaved by the transmembrane serine protease 2 (TMPRSS2) to facilitate viral-host membrane fusion. ACE2 and TMPRSS2 expression profiles have been analyzed at the genomic, transcriptomic, and single-cell RNAseq levels. However, transcriptomic data and actual protein validation convey conflicting information regarding the distribution of the biologically relevant protein receptor in whole tissues. To describe the organ-level architecture of receptor expression, related to the ability of ACE2 and TMPRSS2 to mediate infectivity, we performed a volumetric analysis of whole Syrian hamster lung lobes. Lung tissue of infected and control animals was stained using antibodies against ACE2 and TMPRSS2, combined with SARS-CoV-2 nucleoprotein staining. This was followed by light-sheet microscopy imaging to visualize their expression and related infection patterns. The data demonstrate that infection is restricted to sites containing both ACE2 and TMPRSS2, the latter is expressed in the primary and secondary bronchi whereas ACE2 is predominantly observed in the bronchioles and alveoli. Conversely, infection completely overlaps where ACE2 and TMPRSS2 co-localize in the tertiary bronchi, bronchioles, and alveoli.

          Author summary

          The ongoing COVID19 pandemic necessitates additional tools to study SARS-CoV infection dynamics. This increases our understanding of where these viruses cause infections in the lung, and how essential different receptor molecules are. Here we applied tissue optical clearing and 3D immunofluorescence of whole organs from our best animal model, the Syrian hamster. We describe the organ-level architecture of receptor expression profiles, to visualize how their concerted action mediates SARS-CoV-2 infection patterns.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

            Abstract Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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              Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

              Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: SoftwareRole: Visualization
                Role: InvestigationRole: Resources
                Role: Investigation
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: MethodologyRole: ResourcesRole: SoftwareRole: Supervision
                Role: InvestigationRole: ResourcesRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                7 March 2022
                March 2022
                : 18
                : 3
                Affiliations
                [1 ] Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
                [2 ] Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
                [3 ] Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
                [4 ] Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands
                [5 ] Department of Microbiology and Immunology, Weill Medical College of Cornell University, Ney York City, New York, United States of America
                [6 ] Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
                [7 ] Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, United States of America
                [8 ] Department of Chemistry, University of Georgia, Athens, Georgia, United States of America
                University of Pittsburgh, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-21-01721
                10.1371/journal.ppat.1010340
                8930000
                35255100
                00d569bd-911b-4479-bd2b-ccf8714ec9b5
                © 2022 Tomris et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 7, Tables: 0, Pages: 23
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000781, European Research Council;
                Award ID: 802780
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001722, Koninklijke Nederlandse Akademie van Wetenschappen;
                Award ID: Beijerinck Premium
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: HHSN272201400008C
                Award Recipient :
                Funded by: NWO
                Award ID: VICI
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: INV-002022
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001827, Universiteit van Amsterdam;
                Award ID: UMC AMC Fellowship
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: COVID-19 Wave 2 mAbs grant INV-024617
                Award Recipient :
                R.P.dV is a recipient of an ERC Starting Grant from the European Commission (802780) and a Beijerinck Premium of the Royal Dutch Academy of Sciences. SH was funded by NIH/NIAID (contract number HHSN272201400008C). R.W.S. is funded by the Netherlands Organization for Scientific Research (NWO) with a Vici grant, by the Bill & Melinda Gates Foundation, Collaboration for AIDS Vaccine Discovery (CAVD) grant INV-002022. M.J.vG is funded by a Amsterdam UMC AMC Fellowship a Bill & Melinda Gates Foundation, COVID-19 Wave 2 mAbs grant INV-024617. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
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                2022-03-17
                All relevant data are within the manuscript and its Supporting Information files.
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