SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response.
Jessie Huang, Adam J Hume, Kristine M Abo, Rhiannon B Werder, Carlos Villacorta-Martin, Konstantinos-Dionysios Alysandratos, Mary Lou Beermann, Chantelle Simone-Roach, Jonathan Lindstrom-Vautrin, Judith Olejnik, Ellen L Suder, Esther Bullitt, Anne Hinds, Arjun Sharma, Markus Bosmann, Ruobing Wang, Finn Hawkins, Eric J Burks, Mohsan Saeed, Andrew A Wilson, Elke Mühlberger, Darrell N Kotton
Author Information
Jessie Huang: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Adam J Hume: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
Kristine M Abo: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Rhiannon B Werder: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
Carlos Villacorta-Martin: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA.
Konstantinos-Dionysios Alysandratos: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Mary Lou Beermann: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Chantelle Simone-Roach: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; Pulmonary and Respiratory Diseases, Boston Children's Hospital, Boston, MA 02115, USA.
Jonathan Lindstrom-Vautrin: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA.
Judith Olejnik: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
Ellen L Suder: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA.
Esther Bullitt: Department of Physiology & Biophysics, Boston University, Boston, MA 02118, USA.
Anne Hinds: The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Arjun Sharma: The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany.
Markus Bosmann: The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Center for Thrombosis and Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany; Research Center for Immunotherapy (FZI), University Medical Center, University of Mainz, Mainz, Germany; Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118, USA.
Ruobing Wang: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; Pulmonary and Respiratory Diseases, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Finn Hawkins: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Eric J Burks: Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118, USA.
Mohsan Saeed: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA; Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Andrew A Wilson: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. Electronic address: awilson@bu.edu.
Elke Mühlberger: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA 02118, USA. Electronic address: muehlber@bu.edu.
Darrell N Kotton: Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA; Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA 02118, USA. Electronic address: dkotton@bu.edu.
A hallmark of severe COVID-19 pneumonia is SARS-CoV-2 infection of the facultative progenitors of lung alveoli, the alveolar epithelial type 2 cells (AT2s). However, inability to access these cells from patients, particularly at early stages of disease, limits an understanding of disease inception. Here, we present an in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 by using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture. We find a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-κB signaling and loss of the mature alveolar program. Drug testing confirms the efficacy of remdesivir as well as TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in alveolar cells. Our model system reveals cell-intrinsic responses of a key lung target cell to SARS-CoV-2 infection and should facilitate drug development.
