Cited by 74Viral Infections and Immunology ResearchSingle-cell and spatial transcriptomicsCardiac Fibrosis and Remodeling

Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis

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Mantri, Madhav, Hinchman, Meleana M., McKellar, David W., Wang, Michael F. Z., Cross, Shaun T., Parker, John S. L., De Vlaminck, Iwijn·2022·Nature Cardiovascular Research

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Abstract

ABSTRACT A significant fraction of sudden death in children and young adults is due to myocarditis, an inflammatory disease of the heart, most often caused by viral infection. Here we used integrated single-cell and spatial transcriptomics to create a high-resolution, spatially resolved map of reovirus-induced myocarditis in neonatal murine hearts. We assayed hearts collected at three timepoints after reovirus infection and studied the temporal, spatial, and cellular heterogeneity of host-virus interactions. We further assayed the intestine, the primary site of reovirus infection to establish a full chronology of molecular events that ultimately lead to myocarditis. We implemented targeted enrichment of viral transcripts to establish the cellular targets of the virus in the intestine and the heart. Our data give insight into the cell-type specificity of innate immune responses, and into the transcriptional states of inflamed cardiac cells in reovirus-infected heart. We find that inflamed endothelial cells recruit cytotoxic T cells and undergo pyroptosis in the myocarditic tissue. Analyses of spatially restricted gene expression in myocarditic regions and the border zone around those regions identified immune-mediated cell-type specific injury and stress responses. Overall, we observe a dynamic and complex network of cellular phenotypes and cell-cell interactions associated with viral myocarditis.

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  • Viral myocarditis models (reovirus-induced and coxsackievirus B3-induced) reveal pronounced spatial heterogeneity of myocardial injury, dense immune infiltration, and strong upregulation of interferon-related antiviral pathways.

    “Both viral models, analyzed with spatial and single-cell transcriptomics, reveal pronounced spatial heterogeneity of myocardial injury, dense infiltration by immune cells (notably T cells and macrophages), and strong upregulation of interferon-related antiviral pathways.”

    From Elucidating cardiac fibroblasts heterogeneity and activation during experimental autoimmune myocarditis using spatial transcriptomics. (2025) · cites this paper as [12]

    The sections “Spatiotemporal transcriptomics of reovirus-infected hearts” and “Spatially restricted gene expression in myocarditic tissue” report spatially distinct injury, immune-cell infiltration, and interferon-related responses in the reovirus model. The Discussion says the cited paper did not study the CVB3 model: it describes a separate single-cell study of CVB3 and states that study did not explore spatial restriction or heterogeneity in interferon responses. The claim therefore incorrectly extends the combined spatial and single-cell findings to both models; the reovirus results also place most macrophages outside myocarditic regions at 7 days post-infection. (LLM, conf=0.92)

    Experimental — accuracy not yet measured
  • Both autoimmune and viral myocarditis models demonstrate pivotal roles for myeloid-fibroblast communication and patchy spatial patterns of injury, underscoring shared pathways in tissue remodelling.

    “However, both models demonstrate pivotal roles for myeloid–fibroblast communication and patchy spatial patterns of injury, underscoring shared pathways in tissue remodelling.”

    From Elucidating cardiac fibroblasts heterogeneity and activation during experimental autoimmune myocarditis using spatial transcriptomics. (2025) · cites this paper as [12]

    The section ‘Spatially restricted gene expression in myocarditic tissue’ (page not supplied) reports distinct injured regions in reovirus-infected hearts and a fibroblast Ccl2–macrophage Ccr2 recruitment pathway. The paper studies viral myocarditis, not an autoimmune model, so it does not establish that both models share these patterns or tissue-remodelling pathways. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • The autoimmune EAM model recapitulates immune-driven tissue damage and fibroblast activation, but lacks the direct cytopathic effects and robust early interferon signatures seen in viral myocarditis.

    “In contrast, our autoimmune (EAM) model recapitulates immune-driven tissue damage and fibroblast activation, but lacks the direct cytopathic effects and robust early interferon signatures seen in viral myocarditis.”

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Authors
Mantri, M., Hinchman, M. M., McKellar, D. W., Wang, M. F. Z., Cross, S. T., Parker, J. S. L., & De Vlaminck, I.
Affiliations
Cornell University (US)
Corresponding author
Parker, John S. L.
Venue
Nature Cardiovascular Research
Published
2022-10-10
Volume
1
Issue
10
Pages
946-960
ISSN
2731-0590 (ISSN-L)
OpenAlex
W4304084043
Cited by
74
References
64
Citations by year
2026: 22 · 2025: 17 · 2024: 15 · 2023: 13 · 2022: 7
FWCI
9.05
Type
journal article
Language
en
Open access
Locations
  • Nature Cardiovascular Research (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (DP2AI138242, R21AI144557)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
viral myocarditis, reovirus, host-virus interaction, pyroptosis, endothelial cells, cytotoxic T lymphocytes, intestinal infection, neonatal mouse heart, spatial transcriptomics, single-cell transcriptomics, sudden cardiac death, myocardial injury, cell-cell interactions

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