Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster
Summary: Comorbidities, such as obesity, increase the risk of severe COVID-19. However, the mechanisms underlying severe illnesses in individuals with obesity are poorly understood. Here, we used gene-edited leptin knock out (Leptin−/−) obese hamsters to establish a severe infection model. This mode...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225000975 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832573084939321344 |
|---|---|
| author | Ren-Di Jiang Yun-Zhe Luo Hao-Feng Lin Xiao-Shuang Zheng Wen-Tao Zeng Mei-Qin Liu Hao-Hao Deng Qi Wang Ya-Na Lai Ying Chen Zi-Shuo Guo Ya Zeng Qian-Chun Gong Chen Qiu Mei Dong Xi Wang Zi-Yi Wang Li-Na Ji Pan-Pan Hou Qian Li Xu-Rui Shen Bei Li Yun Gao Ai-Hua Zhang Ting-Ting Jiang Ai-Min Shi Peng Zhou Xin-Hua Lin Zi-Qing Deng Jian-Min Li Zheng-Li Shi |
| author_facet | Ren-Di Jiang Yun-Zhe Luo Hao-Feng Lin Xiao-Shuang Zheng Wen-Tao Zeng Mei-Qin Liu Hao-Hao Deng Qi Wang Ya-Na Lai Ying Chen Zi-Shuo Guo Ya Zeng Qian-Chun Gong Chen Qiu Mei Dong Xi Wang Zi-Yi Wang Li-Na Ji Pan-Pan Hou Qian Li Xu-Rui Shen Bei Li Yun Gao Ai-Hua Zhang Ting-Ting Jiang Ai-Min Shi Peng Zhou Xin-Hua Lin Zi-Qing Deng Jian-Min Li Zheng-Li Shi |
| author_sort | Ren-Di Jiang |
| collection | DOAJ |
| description | Summary: Comorbidities, such as obesity, increase the risk of severe COVID-19. However, the mechanisms underlying severe illnesses in individuals with obesity are poorly understood. Here, we used gene-edited leptin knock out (Leptin−/−) obese hamsters to establish a severe infection model. This model exhibits robust viral replication, severe lung lesions, pronounced clinical symptoms, and fatal infection, mirroring severe COVID-19 in patients with obesity. Using single-cell transcriptomics on lung tissues pre- and post-infection, we found that monocyte-derived alveolar macrophages (MD-AM) play a key role in lung hyper-inflammation, including two unique MD-AM cell fate branches specific to Leptin−/− hamsters. Notably, reduced Trem2-dependent efferocytosis pathways in Leptin−/− hamsters indicated weakened inflammation resolution, consistent with the scRNA-seq data from patients with obesity. In summary, our study highlights the obesity-associated mechanisms underlying severe SARS-CoV-2 infections and establishes a reliable preclinical animal model for developing obesity-specific therapeutics for critical COVID-19. |
| format | Article |
| id | doaj-art-725794ed195d4bec9af8d38e5d741bc4 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-725794ed195d4bec9af8d38e5d741bc42025-02-02T05:29:09ZengElsevieriScience2589-00422025-02-01282111837Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamsterRen-Di Jiang0Yun-Zhe Luo1Hao-Feng Lin2Xiao-Shuang Zheng3Wen-Tao Zeng4Mei-Qin Liu5Hao-Hao Deng6Qi Wang7Ya-Na Lai8Ying Chen9Zi-Shuo Guo10Ya Zeng11Qian-Chun Gong12Chen Qiu13Mei Dong14Xi Wang15Zi-Yi Wang16Li-Na Ji17Pan-Pan Hou18Qian Li19Xu-Rui Shen20Bei Li21Yun Gao22Ai-Hua Zhang23Ting-Ting Jiang24Ai-Min Shi25Peng Zhou26Xin-Hua Lin27Zi-Qing Deng28Jian-Min Li29Zheng-Li Shi30State Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Corresponding authorBGI Research, Beijing, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, ChinaThe First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaThe First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, ChinaBGI Research, Beijing, China; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaBGI Research, Beijing, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, ChinaNational Engineering Research Center of Neuromodulation, School of Aerospace Engineering, Tsinghua University, Beijing, ChinaSchool of Life Sciences, Inner Mongolia University, Hohhot, China; Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Chengdu, ChinaGuangzhou National Laboratory, Guangzhou, ChinaThe First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, ChinaGuangzhou National Laboratory, Guangzhou, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, ChinaState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, ChinaThe First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China; Guangzhou National Laboratory, Guangzhou, China; Corresponding authorState Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; School of Life Sciences, Inner Mongolia University, Hohhot, China; Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China; Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, Chengdu, China; Corresponding authorBGI Research, Beijing, China; Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China; Corresponding authorState Key Laboratory of Reproductive Medicine and Offspring Health, Jiangsu Animal Experimental Center of Medicine and Pharmacy, Animal Core facility, Key Laboratory of Model Animal, Department of Cell Biology, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Corresponding authorWuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; Guangzhou National Laboratory, Guangzhou, China; Corresponding authorSummary: Comorbidities, such as obesity, increase the risk of severe COVID-19. However, the mechanisms underlying severe illnesses in individuals with obesity are poorly understood. Here, we used gene-edited leptin knock out (Leptin−/−) obese hamsters to establish a severe infection model. This model exhibits robust viral replication, severe lung lesions, pronounced clinical symptoms, and fatal infection, mirroring severe COVID-19 in patients with obesity. Using single-cell transcriptomics on lung tissues pre- and post-infection, we found that monocyte-derived alveolar macrophages (MD-AM) play a key role in lung hyper-inflammation, including two unique MD-AM cell fate branches specific to Leptin−/− hamsters. Notably, reduced Trem2-dependent efferocytosis pathways in Leptin−/− hamsters indicated weakened inflammation resolution, consistent with the scRNA-seq data from patients with obesity. In summary, our study highlights the obesity-associated mechanisms underlying severe SARS-CoV-2 infections and establishes a reliable preclinical animal model for developing obesity-specific therapeutics for critical COVID-19.http://www.sciencedirect.com/science/article/pii/S2589004225000975Immune responseVirologyOmics |
| spellingShingle | Ren-Di Jiang Yun-Zhe Luo Hao-Feng Lin Xiao-Shuang Zheng Wen-Tao Zeng Mei-Qin Liu Hao-Hao Deng Qi Wang Ya-Na Lai Ying Chen Zi-Shuo Guo Ya Zeng Qian-Chun Gong Chen Qiu Mei Dong Xi Wang Zi-Yi Wang Li-Na Ji Pan-Pan Hou Qian Li Xu-Rui Shen Bei Li Yun Gao Ai-Hua Zhang Ting-Ting Jiang Ai-Min Shi Peng Zhou Xin-Hua Lin Zi-Qing Deng Jian-Min Li Zheng-Li Shi Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster iScience Immune response Virology Omics |
| title | Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster |
| title_full | Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster |
| title_fullStr | Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster |
| title_full_unstemmed | Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster |
| title_short | Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster |
| title_sort | impaired inflammatory resolution with severe sars cov 2 infection in leptin knock out obese hamster |
| topic | Immune response Virology Omics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225000975 |
| work_keys_str_mv | AT rendijiang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT yunzheluo impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT haofenglin impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT xiaoshuangzheng impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT wentaozeng impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT meiqinliu impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT haohaodeng impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT qiwang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT yanalai impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT yingchen impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT zishuoguo impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT yazeng impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT qianchungong impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT chenqiu impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT meidong impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT xiwang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT ziyiwang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT linaji impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT panpanhou impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT qianli impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT xuruishen impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT beili impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT yungao impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT aihuazhang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT tingtingjiang impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT aiminshi impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT pengzhou impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT xinhualin impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT ziqingdeng impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT jianminli impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster AT zhenglishi impairedinflammatoryresolutionwithseveresarscov2infectioninleptinknockoutobesehamster |