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A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic mice

 Seunghoon Choi  ;  Jusung Lee  ;  Suhyeon Kim  ;  Youn Woo Lee  ;  Gi-Cheon Kim  ;  Seung-Min Hong  ;  Se-Hee An  ;  Hyuna Noh  ;  Kyung Eun Kim  ;  Dain On  ;  Sang Gyu Lee  ;  Hui Jeong Jang  ;  Sung-Hee Kim  ;  Jiseon Kim  ;  Jung Seon Seo  ;  Jeong Jin Kim  ;  In Ho Park  ;  Jooyeon Oh  ;  Da-Jung Kim  ;  Jong-Hwi Yoon  ;  Sang-Hyuk Seok  ;  Yu Jin Lee  ;  Seo Yeon Kim  ;  Young Been Kim  ;  Ji-Yeon Hwang  ;  Hyo-Jung Lee  ;  Hong Bin Kim  ;  Jun Won Park  ;  Jun-Won Yun  ;  Jeon-Soo Shin  ;  Jun-Young Seo  ;  Ki Taek Nam  ;  Kang-Seuk Choi  ;  Ho-Keun Kwon  ;  Ho-Young Lee  ;  Jong Kyoung Kim  ;  Je Kyung Seong 
 EBIOMEDICINE, Vol.99 : 104932, 2024-01 
Journal Title
Issue Date
Animals ; Bronchi ; COVID-19* ; Cricetinae ; Disease Models, Animal ; Ferrets ; Humans ; Leukocytes, Mononuclear ; Lung ; Melphalan* ; Mice ; Mice, Transgenic ; SARS-CoV-2 ; Transforming Growth Factor beta ; gamma-Globulins*
K18-hACE2 TG mice ; Lung inflammation ; SARS-CoV-2 infection ; SPP1 ; TGFβ ; scRNA-seq
Background The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research. Methods In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue. Findings Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1(+) macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGF beta signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes. Interpretation Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGF beta signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Ho-Keun(권호근) ORCID logo https://orcid.org/0000-0003-3175-0376
Kim, Sung-Hee(김성희)
Nam, Ki Taek(남기택)
Seo, Jun Young(서준영) ORCID logo https://orcid.org/0000-0003-4004-2013
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Yoon, Jong-Hwi(윤종휘)
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