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

• Published in: iScience Vol. 28; no. 2; p. 111837
• Main Authors: Jiang, Ren-Di, Luo, Yun-Zhe, Lin, Hao-Feng, Zheng, Xiao-Shuang, Zeng, Wen-Tao, Liu, Mei-Qin, Deng, Hao-Hao, Wang, Qi, Lai, Ya-Na, Chen, Ying, Guo, Zi-Shuo, Zeng, Ya, Gong, Qian-Chun, Qiu, Chen, Dong, Mei, Wang, Xi, Wang, Zi-Yi, Ji, Li-Na, Hou, Pan-Pan, Li, Qian, Shen, Xu-Rui, Li, Bei, Gao, Yun, Zhang, Ai-Hua, Jiang, Ting-Ting, Shi, Ai-Min, Zhou, Peng, Lin, Xin-Hua, Deng, Zi-Qing, Li, Jian-Min, Shi, Zheng-Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2025; Elsevier
• Subjects: Immune response; Omics; Virology; Immune response; Omics; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2025.111837

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. [Display omitted] •Leptin knock out obese hamsters were generated by using CRISPR/Cas9 technology•SARS-CoV-2 infection results in severe pneumonia and death in Leptin−/− obese hamsters•SARS-CoV-2 infection induces attenuated inflammatory resolution in Leptin−/− obese hamsters•Imbalanced Trem1/Trem2 in MD-AMs contribute to obesity-associated severe infection Immune response; Virology; Omics