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      SARS-CoV-2 infection studies in lung organoids identify TSPAN8 as novel mediator

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          Abstract

          SARS coronavirus-2 (SARS-CoV-2) is causing a global pandemic with large variation in COVID-19 disease spectrum. SARS-CoV-2 infection requires host receptor ACE2 on lung epithelium, but epithelial underpinnings of variation are largely unknown. We capitalized on comprehensive organoid assays to report remarkable variation in SARS-CoV-2 infection rates of lung organoids from different subjects. Tropism is highest for TUBA− and MUC5AC-positive organoid cells, but levels of TUBA−, MUC5A−, or ACE2− positive cells do not predict infection rate. We identify surface molecule Tetraspanin 8 (TSPAN8) as novel mediator of SARS-CoV-2 infection, which is not downregulated by this specific virus. TSPAN8 levels, prior to infection, strongly correlate with infection rate and TSPAN8-blocking antibodies diminish SARS-CoV-2 infection. We propose TSPAN8 as novel functional biomarker and potential therapeutic target for COVID-19.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
              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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                Author and article information

                Journal
                Journal ID (nlm-ta): bioRxiv
                Journal ID (publisher-id): BIORXIV
                Title: bioRxiv
                Publisher: Cold Spring Harbor Laboratory
                Publication date (Electronic): 02 June 2021
                Electronic Location Identifier: 2021.06.01.446640
                Affiliations
                [1 ]Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
                [2 ]Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143, USA
                [3 ]UCSF CoLabs, University of California San Francisco, San Francisco, California 94143, USA
                [4 ]School of Life Science, University of Essex, Wivenhoe Park,Colchester C04 3SQ, United Kingdom
                [5 ]Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA
                [6 ]Department of Pathology, University of California, San Francisco, San Francisco, California 94143, USA
                [7 ]Division of Infectious Diseases, University of California, San Francisco, San Francisco, California 94143, USA and Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, California 94143, USA
                [8 ]Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, California 94143, USA
                [9 ]Gladstone Institute of Virology, Department of Medicine, University of California San Francisco, California 94143, USA
                [10 ]Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, California 94143, USA
                [12 ]Chan Zuckerberg Biohub, San Francisco, California 94158, USA
                Author notes

                Author contributions

                LH and JPR: conceived and designed study. LH, SL and KK: performed spectral flow and analyses. LH, KK, SL, OMG: performed organoid experiments. LH and LR: BSL3 work. AS and AJC: scRNAseq experiments and advice. JCL: statistical analyses. LCL: computational analysis of scRNAseq data. LB and DE: advice on antibody staining and lung populations. NKS and MK: H1N1 virus. LH, OMG and KB: microscopy. JZL, VD, SM, MM: patient samples for organoids. GK, DMJ, MM, AJC: (funding) support of their team members. MO: SARS-CoV-2 virus. JRK: surgery lung samples, clinical data discussion. LH, SL, LCL, JPR: figure panels. LH, SL, JPR: manuscript writing. JPR: funding for the study. F, DMJ, MM, MO, MM, AJC, DE, ANS, and JRK: edits on draft manuscript.

                [# ] Correspondence: Jeroen Roose, Department of Anatomy, University of California San Francisco (UCSF) 513 Parnassus Avenue, Room HSW-1326, San Francisco, California 94143-0452, USA; jeroen.roose@ 123456ucsf.edu .
                Article
                DOI: 10.1101/2021.06.01.446640
                PMC ID: 8183007
                PubMed ID: 34100012
                SO-VID: 4d4055d2-3247-4ab5-9366-9f3f9d5f085b
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.

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