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

• Published in: Stem cell reports Vol. 18; no. 3; pp. 636 - 653
• Main Authors: Hysenaj, Lisiena, Little, Samantha, Kulhanek, Kayla, Magnen, Melia, Bahl, Kriti, Gbenedio, Oghenekevwe M., Prinz, Morgan, Rodriguez, Lauren, Andersen, Christopher, Rao, Arjun Arkal, Shen, Alan, Lone, Jean-Christophe, Lupin-Jimenez, Leonard C., Bonser, Luke R., Serwas, Nina K., Mick, Eran, Khalid, Mir M., Taha, Taha Y., Kumar, Renuka, Li, Jack Z., Ding, Vivianne W., Matsumoto, Shotaro, Maishan, Mazharul, Sreekumar, Bharath, Simoneau, Camille, Nazarenko, Irina, Tomlinson, Michael G., Khan, Khajida, von Gottberg, Anne, Sigal, Alex, Looney, Mark R., Fragiadakis, Gabriela K., Jablons, David M., Langelier, Charles R., Matthay, Michael, Krummel, Matthew, Erle, David J., Combes, Alexis J., Sil, Anita, Ott, Melanie, Kratz, Johannes R., Roose, Jeroen P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2023; The Authors
• Subjects: airway organoids; cell composition; COVID-19; H1N1; Humans; Influenza A Virus, H1N1 Subtype; Organoids; SARS-CoV-2; single cell RNAseq; spectral flow; Tetraspanins - genetics; therapeutics; TSPAN8; variants; virus; spectral flow; SARS-CoV-2; therapeutics; TSPAN8; single cell RNAseq; cell composition; variants; H1N1; virus; airway organoids
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2023.01.011

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. •Airway organoids from different donors display distinct compositions of cell types•Organoid biobank models the spectrum of the epithelium response to pathogens•TSPAN8 is a conserved mediator of infection for SARS-CoV-2 variants Roose and colleagues generated a biobank of 20 airway organoids for modeling variations of airway epithelium response to SARS-CoV-2. They discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection independently of ACE2-Spike interaction. Pre-treatment of airway organoids with a blocking TSPAN8 antibody decreased SARS-CoV-2 infection levels in airway organoids, suggesting TSPAN8 as a therapeutic target for COVID-19.