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, Mélia Magnen, Kriti Bahl, Oghenekevwe M. Gbenedio, Morgan Prinz, Lauren Rodriguez, Chris Andersen, Arjun A. Rao, Alan Shen, Jean‐Christophe Lone, Leonard 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 R. Simoneau, Irina Nazarenko, Michael G. Tomlinson, Khadija Khan, Anne von Gottberg, Alex Sigal, Mark R. Looney, Gabriela K. Fragiadakis, David M. Jablons, Charles Langelier, Michael A. Matthay, Matthew F. Krummel, David J. Erle, Alexis J. Combes, Anita Sil, Mélanie Ott, Johannes R. Kratz, Jeroen P. Roose
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.