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Robust three-dimensional expansion of human adult alveolar stem cells and SARS-CoV-2 infection

By Jeonghwan Youk, Taewoo Kim, Kelly V. Evans, Young-Il Jeong, Yongsuk Hur, Seon Pyo Hong, Je Hyoung Kim, Kijong Yi, Su Yeon Kim, Kwon Joong Na, Thomas Bleazard, Ho Min Kim, Natasha Ivory, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Young Tae Kim, Gou Young Koh, Byeong-Sun Choi, Young Seok Ju, Joo-Hyeon Lee

Posted 10 Jul 2020
bioRxiv DOI: 10.1101/2020.07.10.194498

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar cells (hACs). Characterising the pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hACs limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for human alveolar type 2 (hAT2) cells, 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 long-term 3D hAT2 cultures as models for respiratory diseases. ### Competing Interest Statement The authors have declared no competing interest.

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