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Cited by 40Viral Infections and Immunology ResearchCardiac Fibrosis and RemodelingTakotsubo Cardiomyopathy and Associated Phenomena

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Spatiotemporal transcriptomics elucidates the pathogenesis of fulminant viral myocarditis

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Li, Huihui, Chen, Xueting, Wang, James Jiqi, Shen, Juan, Abuduwufuer, Kudusi, Zhang, Zhao, Dong, Zhensheng, Wen, Zheng, He, Jingwei, Chen, Silian, Li, Wanshun, Chen, Chen, Li, Fan, Fang, Xiaodong, Wang, Dao Wen·2025·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-025-02143-9PMC PMC11808084
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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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Figures

Fig. 1 The spatiotemporal landscape of FM mice. a Schematic diagram of the workflow for this study. b UMAP embedding of all the cells colored by manually annotated cell types. c Heatmap showing the expression levels of cell-typing genes in each cell type. The color represents the gene expression level. d Cell component changes among different time points. e Heatmap showing the expression levels of specific functional genes at different time points. The color represents the gene expression level. The spatial structures (f) and infection response score (g) of cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. Scale bar: 500 μm. h Spatial structure proportion changes among different time points. i Heatmap showing the Pearson correlation between cell types defined in snRNA-seq and spatial structures defined in stereo-seq data. j Spatial immune cell infiltration on cardiac tissue sections from CVB3-infected mice at 7 dpi. Scale bar: 500 μm for whole cardiac section, 100 μm for zoomed view. EC endothelial cell, Mac/mono macrophage/monocyte, FB fibroblast, CM cardiomyocyte, PC pericyte, T T cell, Endo endocardial cells, Neu neutrophil, SMC smooth muscle cell, LC lymphatic cell, B B cell, Mes mesothelial cell, NC neuron cell, Adipo adipocyte
Fig. 1 The spatiotemporal landscape of FM mice. a Schematic diagram of the workflow for this study. b UMAP embedding of all the cells colored by manually annotated cell types. c Heatmap showing the expression levels of cell-typing genes in each cell type. The color represents the gene expression level. d Cell component changes among different time points. e Heatmap showing the expression levels of specific functional genes at different time points. The color represents the gene expression level. The spatial structures (f) and infection response score (g) of cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. Scale bar: 500 μm. h Spatial structure proportion changes among different time points. i Heatmap showing the Pearson correlation between cell types defined in snRNA-seq and spatial structures defined in stereo-seq data. j Spatial immune cell infiltration on cardiac tissue sections from CVB3-infected mice at 7 dpi. Scale bar: 500 μm for whole cardiac section, 100 μm for zoomed view. EC endothelial cell, Mac/mono macrophage/monocyte, FB fibroblast, CM cardiomyocyte, PC pericyte, T T cell, Endo endocardial cells, Neu neutrophil, SMC smooth muscle cell, LC lymphatic cell, B B cell, Mes mesothelial cell, NC neuron cell, Adipo adipocyteCC BY · PubMed Central
Fig. 2 Distinct transcriptional patterns of the hearts during FM progression. a Heatmap showing the genes with significant spatial autocorrelation grouped into different modules based on pairwise spatial correlations on cardiac tissue sections. Selected genes and their corresponding GO terms related to representative gene modules are highlighted on the right side. b The expression of module genes on cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. Boxplots of cardiac muscle contraction score (c), cytokine score (d), chemokine score (e) and interferon alpha score (f) of control and CVB3-infected mice from 1 to 7 dpi. g Heatmap of pathway enrichment on different spatial structures. h The pathway activation status on the typical cardiac tissue section of 7 dpi. Scale bar: 500 μm. i The activation status of typical inflammatory pathways in different types of immune cells. j The activation of pathways in the ventricle and myocarditic region at different time points
Fig. 2 Distinct transcriptional patterns of the hearts during FM progression. a Heatmap showing the genes with significant spatial autocorrelation grouped into different modules based on pairwise spatial correlations on cardiac tissue sections. Selected genes and their corresponding GO terms related to representative gene modules are highlighted on the right side. b The expression of module genes on cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. Boxplots of cardiac muscle contraction score (c), cytokine score (d), chemokine score (e) and interferon alpha score (f) of control and CVB3-infected mice from 1 to 7 dpi. g Heatmap of pathway enrichment on different spatial structures. h The pathway activation status on the typical cardiac tissue section of 7 dpi. Scale bar: 500 μm. i The activation status of typical inflammatory pathways in different types of immune cells. j The activation of pathways in the ventricle and myocarditic region at different time pointsCC BY · PubMed Central
Fig. 3 CVB3 infection of cardiac structure cells and immune cells. a The stage delineation of disease progression based on Pearson correlation. b Volcano plot of regulated genes when compare the cells of early and late stages. c Dot plot shows the GO terms of specifically expressed genes in cardiomyocytes of each stage. d Violin plot showing the level of CVB3 in cells of control and CVB3-infected mice heart from 1 to 7 dpi in the snRNA-seq data. e The level of CVB3 in cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. f The proportion of CVB3 positive cells in all cell types in the snRNA-seq data. g The typical image of CVB3 mRNA distribution in the cardiac section. Scale bar: 500 μm. h Violin plot of CVB3 level in different spatial regions. i Bubble plot showing the level of CVB3 in each cell type of control and CVB3-infected mice hearts from 1 to 7 dpi in the snRNA-seq data. j Infection response score for cardiac structure cells in snRNA-seq data across control and CVB3 infected hearts from 1 to 7 dpi. k Representative spatial image of myocarditic region that distributed near the border region from CVB3-infected mice heart at 4 dpi. Scale bar: 500 μm. l Representative spatial image of the distance of myocarditic region to the border region of CVB3-infected mice heart at 4 dpi. Scale bar: 500 μm. m The distance of myocarditic region to the border region of CVB3-infected mice hearts from 1 to 7 dpi. n Immunofluorescence staining of MLSN and CVB3 showing infected mesothelial cells at 1 dpi. Scale bar: 50 μm. o Heatmap showing the number of signaling interaction among immune cells and structural cells in the early stage. p Violin plot showing the expression level of damage-associated molecular pattern genes in mesothelial cells of control and CVB3 infected mice at different stages. q Heatmap shows the expression level of toll-like receptors in major immure cell types. r Heatmap shows the interaction of the CSF signaling pathway among cardiac immune cells and structure cells. EC endothelial cell, Mac/mono macrophage/monocyte, FB fibroblast, CM cardiomyocyte, PC pericyte, T T cell, Endo endocardial cells, Neu neutrophil, SMC smooth muscle cell, LC lymphatic cell, B B cell, Mes mesothelial cell, NC neuron cell, Adipo adipocyte
Fig. 3 CVB3 infection of cardiac structure cells and immune cells. a The stage delineation of disease progression based on Pearson correlation. b Volcano plot of regulated genes when compare the cells of early and late stages. c Dot plot shows the GO terms of specifically expressed genes in cardiomyocytes of each stage. d Violin plot showing the level of CVB3 in cells of control and CVB3-infected mice heart from 1 to 7 dpi in the snRNA-seq data. e The level of CVB3 in cardiac tissue sections from control and CVB3-infected mice from 1 to 7 dpi. f The proportion of CVB3 positive cells in all cell types in the snRNA-seq data. g The typical image of CVB3 mRNA distribution in the cardiac section. Scale bar: 500 μm. h Violin plot of CVB3 level in different spatial regions. i Bubble plot showing the level of CVB3 in each cell type of control and CVB3-infected mice hearts from 1 to 7 dpi in the snRNA-seq data. j Infection response score for cardiac structure cells in snRNA-seq data across control and CVB3 infected hearts from 1 to 7 dpi. k Representative spatial image of myocarditic region that distributed near the border region from CVB3-infected mice heart at 4 dpi. Scale bar: 500 μm. l Representative spatial image of the distance of myocarditic region to the border region of CVB3-infected mice heart at 4 dpi. Scale bar: 500 μm. m The distance of myocarditic region to the border region of CVB3-infected mice hearts from 1 to 7 dpi. n Immunofluorescence staining of MLSN and CVB3 showing infected mesothelial cells at 1 dpi. Scale bar: 50 μm. o Heatmap showing the number of signaling interaction among immune cells and structural cells in the early stage. p Violin plot showing the expression level of damage-associated molecular pattern genes in mesothelial cells of control and CVB3 infected mice at different stages. q Heatmap shows the expression level of toll-like receptors in major immure cell types. r Heatmap shows the interaction of the CSF signaling pathway among cardiac immune cells and structure cells. EC endothelial cell, Mac/mono macrophage/monocyte, FB fibroblast, CM cardiomyocyte, PC pericyte, T T cell, Endo endocardial cells, Neu neutrophil, SMC smooth muscle cell, LC lymphatic cell, B B cell, Mes mesothelial cell, NC neuron cell, Adipo adipocyteCC BY · PubMed Central
Fig. 4 Macrophages chemotaxis activate cytotoxic T cells. a Spatial transcriptomic map of cardiac tissue section from CVB3-infected mice at 6 dpi colored by spot clusters representing transcriptionally distinct tissue regions. Scale bar: 500 μm. b Changes in average predicted fibroblast proportion across the infected ventricle. c Spatial distribution of fibroblast (left) and the expression of Bgn on the spatial section (right). d Box plot of ECM score among ventricle region, border zone and myocarditic region (left) and ECM score on the spatial section (right). e Changes in average predicted cell type proportions across the infected ventricle. f UMAP embedding of macrophages colored by manually annotated clusters. Box plot of pro-inflammatory (g) and chemokine (h) scores among different macrophage subclusters. Scores were calculated by AddModuleScore function of the Seurat package. i UMAP embedding shows the developmental trajectory of macrophage subclusters. j The densities of Mono_Ccr2, Mac_IFNIC and Inflammatory_Mac along the developmental trajectory. k The expression of Ccl3 and Cxcl2 along the developmental trajectory. l UMAP embedding of T cells colored by manually annotated clusters. m The number of T cell subpopulations during disease progression. n The functional gene sets and Ifng expression level in T cell subpopulations. o The interaction pathways between Inflammatory_Mac and Cd8+ effector T. p The spatial colocation of Inflammatory_Mac and Cd8+ effector T cells. Red means the abundance of Inflammatory_Mac, green means the abundance of Cd8+ effector T, yellow means the colocation of two cell types. Scale bar: 500 μm. Ven ventricle, BZ border zone, MR myocarditic region
Fig. 4 Macrophages chemotaxis activate cytotoxic T cells. a Spatial transcriptomic map of cardiac tissue section from CVB3-infected mice at 6 dpi colored by spot clusters representing transcriptionally distinct tissue regions. Scale bar: 500 μm. b Changes in average predicted fibroblast proportion across the infected ventricle. c Spatial distribution of fibroblast (left) and the expression of Bgn on the spatial section (right). d Box plot of ECM score among ventricle region, border zone and myocarditic region (left) and ECM score on the spatial section (right). e Changes in average predicted cell type proportions across the infected ventricle. f UMAP embedding of macrophages colored by manually annotated clusters. Box plot of pro-inflammatory (g) and chemokine (h) scores among different macrophage subclusters. Scores were calculated by AddModuleScore function of the Seurat package. i UMAP embedding shows the developmental trajectory of macrophage subclusters. j The densities of Mono_Ccr2, Mac_IFNIC and Inflammatory_Mac along the developmental trajectory. k The expression of Ccl3 and Cxcl2 along the developmental trajectory. l UMAP embedding of T cells colored by manually annotated clusters. m The number of T cell subpopulations during disease progression. n The functional gene sets and Ifng expression level in T cell subpopulations. o The interaction pathways between Inflammatory_Mac and Cd8+ effector T. p The spatial colocation of Inflammatory_Mac and Cd8+ effector T cells. Red means the abundance of Inflammatory_Mac, green means the abundance of Cd8+ effector T, yellow means the colocation of two cell types. Scale bar: 500 μm. Ven ventricle, BZ border zone, MR myocarditic regionCC BY · PubMed Central
Fig. 5 Cd8+ effector T cells induced the damage of cardiomyocytes. a Changes in average predicted proportion of cardiomyocytes across the infected ventricle in the late stage. b The expression of apoptosis, necroptosis, and pyroptosis genes during disease progression in the snRNA-seq data. c UMAP embedding of cardiomyocytes of the snRNA-seq data colored by manually annotated clusters. d Cell proportion changes of cardiomyocytes at different time points. e Box plots of death score and heart contraction score among different cardiomyocyte subclusters. Scores were calculated by AddModuleScore function of the Seurat package. f The spatial colocation of contraction genes and T cell cytotoxicity genes. Green means the expression of cardiac contraction genes, red means the expression of cardiac T cell cytotoxicity genes, and yellow means the co-expression status. Scale bar: 500 μm. g Box plots of apoptosis, pyroptosis, and necroptosis scores between cardiomyocytes that are near to Cd8+ effector T cells and those distant to Cd8+ effector T cells. h The spatial colocation of virus--death+ cells and Cd8+ effector T cells. Green means the abundance of virus--death+ CMs, red means the abundance of Cd8+ effector T cells, and yellow means the colacation of the two cell types. Scale bar: 500 μm. i Expression trend of Ifng in T cells along different infection times (fitted with loess). The line shadow showing the 95% confidence interval. j Western blot images of representative death genes expression in the vehicle and IFN-γ treated mouse primary cardiomyocytes. k The top regulons that activated in virus--deathhigh CMs. l The expression of key transcriptional factors in the heart of patients with FM (n = 3 in HC group, n = 4 in FM group, data are represented as mean ± SEM). m The expression of Spi1 in the heart of FM mice and control (n = 5 per group, data are represented as mean ± SEM). n The expression of Spi1 in IFN-γ treated mouse primary cardiomyocytes (n = 4 per group, data are represented as mean ± SEM). o Correlation between response to interferon gamma score and Spi1 AUCell score of cardiomyocytes. p The mRNA level changes of death genes in IFN-γ and si-Spi1 treated mouse primary cardiomyocytes (n = 4 per group, data are represented as mean ± SEM). q Protein level changes of death genes in IFN-γ and si-Spi1 treated mouse primary cardiomyocytes. Survival rate (r), H&E staining images (s), representative echocardiography images (t) and cardiac functions (ejection fraction and fraction shortening) (u) changes of FM and Spi1 inhibitor-treated mice. (n = 5 per group, data are represented as mean ± SEM). Scale bar: 500 μm. Ven ventricle, BZ border zone, MR myocarditic region, HC healthy control, FM fulminant myocarditis
Fig. 5 Cd8+ effector T cells induced the damage of cardiomyocytes. a Changes in average predicted proportion of cardiomyocytes across the infected ventricle in the late stage. b The expression of apoptosis, necroptosis, and pyroptosis genes during disease progression in the snRNA-seq data. c UMAP embedding of cardiomyocytes of the snRNA-seq data colored by manually annotated clusters. d Cell proportion changes of cardiomyocytes at different time points. e Box plots of death score and heart contraction score among different cardiomyocyte subclusters. Scores were calculated by AddModuleScore function of the Seurat package. f The spatial colocation of contraction genes and T cell cytotoxicity genes. Green means the expression of cardiac contraction genes, red means the expression of cardiac T cell cytotoxicity genes, and yellow means the co-expression status. Scale bar: 500 μm. g Box plots of apoptosis, pyroptosis, and necroptosis scores between cardiomyocytes that are near to Cd8+ effector T cells and those distant to Cd8+ effector T cells. h The spatial colocation of virus--death+ cells and Cd8+ effector T cells. Green means the abundance of virus--death+ CMs, red means the abundance of Cd8+ effector T cells, and yellow means the colacation of the two cell types. Scale bar: 500 μm. i Expression trend of Ifng in T cells along different infection times (fitted with loess). The line shadow showing the 95% confidence interval. j Western blot images of representative death genes expression in the vehicle and IFN-γ treated mouse primary cardiomyocytes. k The top regulons that activated in virus--deathhigh CMs. l The expression of key transcriptional factors in the heart of patients with FM (n = 3 in HC group, n = 4 in FM group, data are represented as mean ± SEM). m The expression of Spi1 in the heart of FM mice and control (n = 5 per group, data are represented as mean ± SEM). n The expression of Spi1 in IFN-γ treated mouse primary cardiomyocytes (n = 4 per group, data are represented as mean ± SEM). o Correlation between response to interferon gamma score and Spi1 AUCell score of cardiomyocytes. p The mRNA level changes of death genes in IFN-γ and si-Spi1 treated mouse primary cardiomyocytes (n = 4 per group, data are represented as mean ± SEM). q Protein level changes of death genes in IFN-γ and si-Spi1 treated mouse primary cardiomyocytes. Survival rate (r), H&E staining images (s), representative echocardiography images (t) and cardiac functions (ejection fraction and fraction shortening) (u) changes of FM and Spi1 inhibitor-treated mice. (n = 5 per group, data are represented as mean ± SEM). Scale bar: 500 μm. Ven ventricle, BZ border zone, MR myocarditic region, HC healthy control, FM fulminant myocarditisCC BY · PubMed Central
Fig. 6 The treatment effects of IVIG on FM mice. a Schematic diagram of the workflow for drug administration. b PCA analysis of control, infection and treatment samples from 1 to 7dpi. c The level of inflammation score in control, infection and treatment samples from 1 to 7dpi. d The level of CVB3 in control, infection and treatment samples from 1 to 7dpi. e Heatmap showing the expression level of PC1 genes. f Violin plot shows the expression of PC1 genes in different spatial areas. g The proportion of Mono_Ccr2, Mac_IFNIC and Inflammatory_Mac of infection and treatment groups. h Differential strength of cellular interactions among cardiac macrophages and T cells in infection and treatment groups. The blue line indicates a decrease in the treatment group. i The expression of chemokines (Ccl2 and Ccl4) by Inflammatory_Mac in infection and treatment groups at different stages. j The level of CVB3, the expression of Ccl2 and Ccr2, and the distribution of Inflammatory_Mac and Cd8+ effector T cells on cardiac sections in treatment group in the late stage. k The proportion of Cd8+ effector T cells in infection and treatment groups. l The expression of cytotoxic molecules (Fasl and Gzmb) by Cd8+ effector T cells in infection and treatment groups at different stages. m Expression trend of Ifng in T cells of infection and treatment groups along different infection time (fitted with loess). The line shadow showing the 95% confidence interval. n The AUCell score of Spi1 in control, infection and treatment groups. PC principle component
Fig. 6 The treatment effects of IVIG on FM mice. a Schematic diagram of the workflow for drug administration. b PCA analysis of control, infection and treatment samples from 1 to 7dpi. c The level of inflammation score in control, infection and treatment samples from 1 to 7dpi. d The level of CVB3 in control, infection and treatment samples from 1 to 7dpi. e Heatmap showing the expression level of PC1 genes. f Violin plot shows the expression of PC1 genes in different spatial areas. g The proportion of Mono_Ccr2, Mac_IFNIC and Inflammatory_Mac of infection and treatment groups. h Differential strength of cellular interactions among cardiac macrophages and T cells in infection and treatment groups. The blue line indicates a decrease in the treatment group. i The expression of chemokines (Ccl2 and Ccl4) by Inflammatory_Mac in infection and treatment groups at different stages. j The level of CVB3, the expression of Ccl2 and Ccr2, and the distribution of Inflammatory_Mac and Cd8+ effector T cells on cardiac sections in treatment group in the late stage. k The proportion of Cd8+ effector T cells in infection and treatment groups. l The expression of cytotoxic molecules (Fasl and Gzmb) by Cd8+ effector T cells in infection and treatment groups at different stages. m Expression trend of Ifng in T cells of infection and treatment groups along different infection time (fitted with loess). The line shadow showing the 95% confidence interval. n The AUCell score of Spi1 in control, infection and treatment groups. PC principle componentCC BY · PubMed Central

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Research works printed but not linked: 1

  1. Li, M. et al. StereoCell enables highly accurate single-cell segmentation for spatial transcriptomics. bioRxiv, 2023.2002.2028.530414 (2023).

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Metadata

Authors
Li, H., Chen, X., Wang, J. J., Shen, J., Abuduwufuer, K., Zhang, Z., Dong, Z., Wen, Z., He, J., Chen, S., Li, W., Chen, C., Li, F., Fang, X., & Wang, D. W.
Affiliations
  • Tongji Hospital (CN)
  • Chinese Academy of Sciences (CN)
  • BGI Research (CN)
  • MGI (CN)
  • Guangzhou University of Chinese Medicine (CN)
Corresponding author
  • Fang, Xiaodong
  • Wang, Dao Wen
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2025-02-10
Volume
10
Issue
1
Pages
59-59
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-025-02143-9
PMC
PMC11808084
OpenAlex
W4407284214
Cited by
40
References
65
Citations by year
2026: 24 · 2025: 16
FWCI
27.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (82330010, 82241034)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Takotsubo Cardiomyopathy and Associated Phenomena
Keywords
fulminant myocarditis, coxsackievirus B3, mesothelial cells, macrophage activation, T cell infiltration, CD8+ effector T cells, cardiomyocyte injury, interferon-gamma, PU.1, intravenous immunoglobulin, hyperinflammation, A/J mice, sudden cardiac death
MeSH terms
Animals, Coxsackievirus Infections, Disease Models, Animal, Humans, Interferon-gamma, Macrophages, Male, Myocarditis, Proto-Oncogene Proteins, Trans-Activators, Immunoglobulins, Intravenous, CD8-Positive T-Lymphocytes, Enterovirus B, Human, Myocytes, Cardiac, Mice, Transcriptome

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