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  3. Spatiotemporal transcriptomics elucidates the pathogenesis of fulminant viral myocarditis

Spatiotemporal transcriptomics elucidates the pathogenesis of fulminant viral myocarditis

  • Signal Transduct Target Ther. 2025 Feb 10;10(1):59. doi: 10.1038/s41392-025-02143-9.
Huihui Li # 1,  Xueting Chen # 2 3,  James Jiqi Wang # 1,  Juan Shen # 2 4,  Kudusi Abuduwufuer 1,  Zhao Zhang 2 3,  Zhensheng Dong 2,  Zheng Wen 1,  Jingwei He 5,  Silian Chen 2 3,  Wanshun Li 5,  Chen Chen 1,  Fan Li 1,  Xiaodong Fang 6 7,  Dao Wen Wang 8
Affiliations

Affiliations

  • 1 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China.
  • 2 BGI Research, Shenzhen, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 4 Lars Bolund Institute of Regenerative Medicine Qingdao-Europe Advanced Institute for LifeSciences, BGI Research, Qingdao, China.
  • 5 MGI Tech, Shenzhen, China.
  • 6 BGI Research, Sanya, China. [email protected].
  • 7 State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China. [email protected].
  • 8 Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 39924580 DOI: 10.1038/s41392-025-02143-9
Abstract

Fulminant myocarditis (FM) is a severe inflammatory condition of the myocardium that often results in sudden death, particularly in young individuals. In this study, we employed single-nucleus and spatial transcriptomics to perform a comprehensive analysis of coxsackievirus B3 (CVB3)-induced FM in A/J mice, spanning seven distinct time points pre- and post-treatment. Our findings reveal that mesothelial cells play a critical role in the early stage of myocarditis by acting as primary targets for CVB3 Infection. This triggers the activation of macrophages, initiating a cascade of inflammation. Subsequently, pro-inflammatory Inflammatory_Mac and T cells infiltrate the myocardium, driving tissue damage. We also identified Cd8+ effector T cells as key mediators of cardiomyocyte injury. These cells release cytotoxic molecules, particularly IFN-γ, which modulates the expression of Spi1, a factor implicated in exacerbating cardiomyocyte death and amplifying disease progression. Therapeutic interventions targeting the IFN-γ/Spi1 axis demonstrated significant efficacy in FM models. Notably, intravenous immunoglobulin (IVIG) treatment reduced mortality, suppressed viral proliferation, and mitigated the hyperinflammatory state of FM. IVIG therapy also downregulated IFN-γ and Spi1 expression, underscoring its immunomodulatory and therapeutic potential. This comprehensive spatiotemporal transcriptomic analysis provides profound insights into the pathogenesis of FM and highlights actionable therapeutic targets, paving the way for more effective management strategies for this life-threatening condition.

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