A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context
Summary: 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...
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Elsevier
2024-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239642300498X |
| _version_ | 1827577640933916672 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Seunghoon Choi |
| collection | DOAJ |
| description | Summary: 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 TGFβ 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 TGFβ 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. Funding: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501). |
| first_indexed | 2024-03-08T21:30:41Z |
| format | Article |
| id | doaj.art-f2f106e6b5e741e4b13b71bb0cdd0c4a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T21:30:41Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-f2f106e6b5e741e4b13b71bb0cdd0c4a2023-12-21T07:32:51ZengElsevierEBioMedicine2352-39642024-01-0199104932A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in contextSeunghoon Choi0Jusung Lee1Suhyeon Kim2Youn Woo Lee3Gi-Cheon Kim4Seung-Min Hong5Se-Hee An6Hyuna Noh7Kyung Eun Kim8Dain On9Sang Gyu Lee10Hui Jeong Jang11Sung-Hee Kim12Jiseon Kim13Jung Seon Seo14Jeong Jin Kim15In Ho Park16Jooyeon Oh17Da-Jung Kim18Jong-Hwi Yoon19Sang-Hyuk Seok20Yu Jin Lee21Seo Yeon Kim22Young Been Kim23Ji-Yeon Hwang24Hyo-Jung Lee25Hong Bin Kim26Jun Won Park27Jun-Won Yun28Jeon-Soo Shin29Jun-Young Seo30Ki Taek Nam31Kang-Seuk Choi32Ho-Keun Kwon33Ho-Young Lee34Jong Kyoung Kim35Je Kyung Seong36Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 Project for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of KoreaDepartment of New Biology, DGIST, Daegu 42988, Republic of KoreaKorea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of Korea; BIO-MAX Institute, Seoul National University, Seoul 08826, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 23488, Republic of KoreaInstitute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaLaboratory of Avian Diseases, BK21 Project for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of KoreaLaboratory of Avian Diseases, BK21 Project for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of KoreaKorea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of KoreaLaboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 Project for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of KoreaLaboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 Project for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of KoreaKorea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of Korea; Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul 08826, Republic of KoreaDepartment of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 23488, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaGraduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaGraduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaInstitute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaDivision of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24342, Republic of KoreaDivision of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24342, Republic of KoreaPreclinical Research Center, Seoul National University Bundang Hospital, Seongnam 23488, Republic of KoreaPreclinical Research Center, Seoul National University Bundang Hospital, Seongnam 23488, Republic of KoreaPreclinical Research Center, Seoul National University Bundang Hospital, Seongnam 23488, Republic of KoreaDepartment of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam 23620, Republic of KoreaDepartment of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 23620, Republic of KoreaDivision of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24342, Republic of KoreaLaboratory of Veterinary Toxicology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Biomedical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaLaboratory of Avian Diseases, BK21 Project for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Corresponding authors. College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.Graduate School of Medical Science, BK21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Department of Microbiology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Corresponding author. Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 23488, Republic of Korea; Department of Nuclear Medicine, Seoul National University, College of Medicine, Seoul 03080, South Korea; Corresponding author. Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 13488, Republic of Korea.Department of New Biology, DGIST, Daegu 42988, Republic of Korea; Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Corresponding authors. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 Project for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea; Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of Korea; BIO-MAX Institute, Seoul National University, Seoul 08826, Republic of Korea; Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul 08826, Republic of Korea; Corresponding authors. Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Republic of Korea.Summary: 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 TGFβ 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 TGFβ 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. Funding: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).http://www.sciencedirect.com/science/article/pii/S235239642300498XSARS-CoV-2 infectionK18-hACE2 TG micescRNA-seqLung inflammationTGFβSPP1 |
| spellingShingle | 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 A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context EBioMedicine SARS-CoV-2 infection K18-hACE2 TG mice scRNA-seq Lung inflammation TGFβ SPP1 |
| title | A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context |
| title_full | A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context |
| title_fullStr | A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context |
| title_full_unstemmed | A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context |
| title_short | A longitudinal molecular and cellular lung atlas of lethal SARS-CoV-2 infection in K18-hACE2 transgenic miceResearch in context |
| title_sort | longitudinal molecular and cellular lung atlas of lethal sars cov 2 infection in k18 hace2 transgenic miceresearch in context |
| topic | SARS-CoV-2 infection K18-hACE2 TG mice scRNA-seq Lung inflammation TGFβ SPP1 |
| url | http://www.sciencedirect.com/science/article/pii/S235239642300498X |
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