한빛사 논문
Jeonghwan Youk1,2,14, Taewoo Kim1,14, Kelly V. Evans3,4,14, Young-Il Jeong5,14, Yongsuk Hur6,14, Seon Pyo Hong7,14, Je Hyoung Kim5, Kijong Yi1, Su Yeon Kim1, Kwon Joong Na8, Thomas Bleazard9, Ho Min Kim1,10, Mick Fellows11, Krishnaa T. Mahbubani12, Kourosh Saeb-Parsy12, Seon Young Kim13, Young Tae Kim8,*, Gou Young Koh7,*, Byeong-Sun Choi5,*, Young Seok Ju1,2,15,*, Joo-Hyeon Lee3,4,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
2GENOME INSIGHT Inc., Daejeon 34051, Republic of Korea
3Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, CB2 A0W, United Kingdom
4Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EL, United Kingdom
5Division of Viral Disease Research, Center for Infectious Diseases Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju 28159, Republic of Korea
6BioMedical Research Center, Korea Advanced institute of Science and Technology, Daejeon 34141, Republic of Korea
7Center for Vascular Research, Institute for Basic Science, Daejeon 34126, Republic of Korea
8Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul 03080, Republic of Korea
9The National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, United Kingdom
10Center for Biomolecular and Cellular Structure, Institute for Basic Science, Daejeon 34126, Republic of Korea
11Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
12Department of Surgery and Cambridge NIHR Biomedical Research Centre, Biomedical Campus, University of Cambridge, Cambridge, CB2 2QQ, United Kingdom
13Department of Laboratory Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
14These authors contributed equally
15Lead Contact
*Corresponding author
Abstract
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.
Key words : Human lung alveolar type 2 cells; SARS-CoV-2; COVID-19; Virus; 3D cultures; Transcriptome; Pathogenesis; Single-cell RNA-seq; Interferon
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