SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery
Apoorva Mulay,
Bindu Konda,
Gustavo Garcia, Jr.,
Changfu Yao,
Stephen Beil,
Jaquelyn M. Villalba,
Colin Koziol,
Chandani Sen,
Arunima Purkayastha,
Jay. K. Kolls,
Derek A. Pociask,
Patrizia Pessina,
Julio Sainz de Aja,
Carolina Garcia-de-Alba,
Carla F. Kim,
Brigitte Gomperts,
Vaithilingaraja Arumugaswami,
Barry R. Stripp
Affiliations
Apoorva Mulay
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Bindu Konda
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Gustavo Garcia, Jr.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
Changfu Yao
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Stephen Beil
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Jaquelyn M. Villalba
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; California State University, Long Beach, CA, USA
Colin Koziol
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Chandani Sen
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Arunima Purkayastha
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
Jay. K. Kolls
Tulane School of Medicine, New Orleans, LA 70112, USA
Derek A. Pociask
Tulane School of Medicine, New Orleans, LA 70112, USA
Patrizia Pessina
Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Julio Sainz de Aja
Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Carolina Garcia-de-Alba
Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Carla F. Kim
Stem Cell Program and Divisions of Hematology/Oncology and Pulmonary & Respiratory Diseases, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
Brigitte Gomperts
UCLA Children’s Discovery and Innovation Institute, Mattel Children’s Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad, Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA
Vaithilingaraja Arumugaswami
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA; Eli and Edythe Broad, Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Corresponding author
Barry R. Stripp
Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Corresponding author
Summary: Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens.
