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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis

Madhav Mantri, Meleana M. Hinchman, View ORCID ProfileDavid W. McKellar, Michael F. Z. Wang, Shaun T. Cross, John S. L. Parker, Iwijn De Vlaminck
doi: https://doi.org/10.1101/2021.12.07.471659
Madhav Mantri
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
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Meleana M. Hinchman
2Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York
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David W. McKellar
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
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  • ORCID record for David W. McKellar
Michael F. Z. Wang
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
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Shaun T. Cross
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
2Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York
3Cornell Institute for Host-Microbe Interactions and Disease, Cornell University, Ithaca, New York
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John S. L. Parker
2Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York
3Cornell Institute for Host-Microbe Interactions and Disease, Cornell University, Ithaca, New York
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  • For correspondence: vlaminck@cornell.edu jsp7@cornell.edu
Iwijn De Vlaminck
1Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
3Cornell Institute for Host-Microbe Interactions and Disease, Cornell University, Ithaca, New York
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  • For correspondence: vlaminck@cornell.edu jsp7@cornell.edu
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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 that recruit circulating immune cells, including cytotoxic T cells which induce 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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • 1. Additional validation experiment data to 3 figures. 2. Additional data panels to 11 supplementary figures. 3. Supplement file updated.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 11, 2022.
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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis
Madhav Mantri, Meleana M. Hinchman, David W. McKellar, Michael F. Z. Wang, Shaun T. Cross, John S. L. Parker, Iwijn De Vlaminck
bioRxiv 2021.12.07.471659; doi: https://doi.org/10.1101/2021.12.07.471659
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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis
Madhav Mantri, Meleana M. Hinchman, David W. McKellar, Michael F. Z. Wang, Shaun T. Cross, John S. L. Parker, Iwijn De Vlaminck
bioRxiv 2021.12.07.471659; doi: https://doi.org/10.1101/2021.12.07.471659

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