Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster

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

doi:10.1016/j.isci.2025.111837

Impaired inflammatory resolution with severe SARS-CoV-2 infection in leptin knock out obese hamster

iScience. 2025 Jan 17;28(2):111837. doi: 10.1016/j.isci.2025.111837. eCollection 2025 Feb 21.

Authors

Ren-Di Jiang¹, Yun-Zhe Luo^{2

3}, Hao-Feng Lin^{4

5}, Xiao-Shuang Zheng⁵, Wen-Tao Zeng⁶, Mei-Qin Liu⁵, Hao-Hao Deng^{2

7}, Qi Wang^{4

3}, Ya-Na Lai⁶, Ying Chen⁴, Zi-Shuo Guo^{4

3}, Ya Zeng^{2

3}, Qian-Chun Gong¹, Chen Qiu⁶, Mei Dong⁶, Xi Wang^{4

3}, Zi-Yi Wang⁸, Li-Na Ji^{9

10}, Pan-Pan Hou¹¹, Qian Li⁵, Xu-Rui Shen¹¹, Bei Li⁴, Yun Gao⁶, Ai-Hua Zhang⁶, Ting-Ting Jiang⁴, Ai-Min Shi⁶, Peng Zhou^{5

11}, Xin-Hua Lin^{1

9

12

10}, Zi-Qing Deng^{2

7}, Jian-Min Li⁶, Zheng-Li Shi^{4

11}

Affiliations

¹ State Key Laboratory of Genetic Engineering, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
² BGI Research, Beijing, China.
³ College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
⁴ Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
⁵ The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
⁶ State 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.
⁷ Shenzhen Key Laboratory of Unknown Pathogen Identification, BGI-Shenzhen, Shenzhen, China.
⁸ National Engineering Research Center of Neuromodulation, School of Aerospace Engineering, Tsinghua University, Beijing, China.
⁹ School of Life Sciences, Inner Mongolia University, Hohhot, China.
¹⁰ 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.
¹¹ Guangzhou National Laboratory, Guangzhou, China.
¹² Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China.

Abstract

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.

Keywords: Immune response; Omics; Virology.