SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants

Lisiena Hysenaj; Samantha Little; Kayla Kulhanek; Melia Magnen; Kriti Bahl; Oghenekevwe M Gbenedio; Morgan Prinz; Lauren Rodriguez; Christopher Andersen; Arjun Arkal Rao; Alan Shen; Jean-Christophe Lone; Leonard C Lupin-Jimenez; Luke R Bonser; Nina K Serwas; Eran Mick; Mir M Khalid; Taha Y Taha; Renuka Kumar; Jack Z Li; Vivianne W Ding; Shotaro Matsumoto; Mazharul Maishan; Bharath Sreekumar; Camille Simoneau; Irina Nazarenko; Michael G Tomlinson; Khajida Khan; Anne von Gottberg; Alex Sigal; Mark R Looney; Gabriela K Fragiadakis; David M Jablons; Charles R Langelier; Michael Matthay; Matthew Krummel; David J Erle; Alexis J Combes; Anita Sil; Melanie Ott; Johannes R Kratz; Jeroen P Roose

doi:10.1016/j.stemcr.2023.01.011

SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants

Stem Cell Reports. 2023 Mar 14;18(3):636-653. doi: 10.1016/j.stemcr.2023.01.011. Epub 2023 Feb 23.

Authors

Lisiena Hysenaj¹, Samantha Little¹, Kayla Kulhanek¹, Melia Magnen², Kriti Bahl¹, Oghenekevwe M Gbenedio¹, Morgan Prinz¹, Lauren Rodriguez³, Christopher Andersen⁴, Arjun Arkal Rao⁵, Alan Shen⁶, Jean-Christophe Lone⁷, Leonard C Lupin-Jimenez⁴, Luke R Bonser⁸, Nina K Serwas⁹, Eran Mick¹⁰, Mir M Khalid¹¹, Taha Y Taha¹¹, Renuka Kumar¹¹, Jack Z Li¹², Vivianne W Ding¹², Shotaro Matsumoto¹³, Mazharul Maishan¹³, Bharath Sreekumar¹¹, Camille Simoneau¹¹, Irina Nazarenko¹⁴, Michael G Tomlinson¹⁵, Khajida Khan¹⁶, Anne von Gottberg¹⁷, Alex Sigal¹⁸, Mark R Looney¹⁹, Gabriela K Fragiadakis²⁰, David M Jablons²¹, Charles R Langelier²², Michael Matthay²³, Matthew Krummel²⁴, David J Erle²⁵, Alexis J Combes⁵, Anita Sil²⁶, Melanie Ott²⁷, Johannes R Kratz²⁸, Jeroen P Roose²⁹

Affiliations

¹ Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
² ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA.
⁴ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA.
⁵ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ School of Life Science, University of Essex, C04 3SQ Colchester, UK.
⁸ Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁹ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA; Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
¹¹ Gladstone Institute of Virology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹² Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA.
¹³ Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Institute for Infection Prevention and Hospital Epidemiology, University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; German Cancer Consortium, Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany.
¹⁵ School of Biosciences, University of Birmingham, Birmingham, UK; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, Midlands, UK.
¹⁶ Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
¹⁷ National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa; SAMRC Antibody Immunity Research Unit, University of the Witwatersrand, Johannesburg, South Africa.
¹⁸ Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Max Planck Institute for Infection Biology, Berlin, Germany; Centre for the AIDS Program of Research, Durban, South Africa.
¹⁹ ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA.
²⁰ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA 94143, USA.
²¹ Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA; Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, CA 94143, USA.
²² Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA; Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA; Gladstone Institute of Virology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
²³ Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁴ Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁵ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Division of Pulmonary and Critical Care, San Francisco, San Francisco, CA, USA.
²⁶ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁷ Gladstone Institute of Virology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA 94143, USA; Quantitative Biosciences Institute COVID-19 Research Group, University of California, San Francisco, San Francisco, CA, USA.
²⁸ ImmunoX Initiative, University of California, San Francisco, San Francisco, CA, USA; Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA.
²⁹ Department of Anatomy, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: jeroen.roose@ucsf.edu.

Abstract

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.

Keywords: H1N1; SARS-CoV-2; TSPAN8; airway organoids; cell composition; single cell RNAseq; spectral flow; therapeutics; variants; virus.

Publication types

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

MeSH terms

COVID-19*
Humans
Influenza A Virus, H1N1 Subtype*
Organoids
SARS-CoV-2
Tetraspanins / genetics

SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants

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