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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis.

ABSTRACT: A significant fraction of sudden death in children and young adults is due to viral myocarditis, an inflammatory disease of the heart. In this study, by using integrated single-cell and spatial transcriptomics, we created a high-resolution, spatially resolved transcriptome map of reovirus-induced myocarditis in neonatal mouse hearts. We assayed hearts collected at three timepoints after 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 found 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 identified immune-mediated cell-type-specific injury and stress responses. Overall, we observed a complex network of cellular phenotypes and spatially restricted cell-cell interactions associated with reovirus-induced myocarditis in neonatal mice.

SUBMITTER: Mantri M

PROVIDER: S-EPMC10035375 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis.

Mantri Madhav M Hinchman Meleana M MM McKellar David W DW Wang Michael F Z MFZ Cross Shaun T ST Parker John S L JSL De Vlaminck Iwijn I

Nature cardiovascular research 20221010 10

A significant fraction of sudden death in children and young adults is due to viral myocarditis, an inflammatory disease of the heart. In this study, by using integrated single-cell and spatial transcriptomics, we created a high-resolution, spatially resolved transcriptome map of reovirus-induced myocarditis in neonatal mouse hearts. We assayed hearts collected at three timepoints after infection and studied the temporal, spatial and cellular heterogeneity of host-virus interactions. We further ...[more]

PMID: 36970396

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Project description:Simple Summary Myocarditis is the inflammation of the heart muscle, and viral infections are a common cause of this disease. Myocarditis in some patients can progress to dilated cardiomyopathy (DCM). The mouse model of coxsackievirus B3 (CVB3) is commonly used to understand this disease progression in DCM patients. In this paper, we have attempted to analyze antibodies for heart antigens that could be produced as a result of heart damage in animals infected with CVB3 using a technique called Phage ImmunoPrecipitation Sequencing (PhIP-Seq). The analyses led us to identify antibodies for several proteins that were not previously reported that may have relevance to human disease. Abstract Enteroviruses such as group B coxsackieviruses (CVB) are commonly suspected as causes of myocarditis that can lead to dilated cardiomyopathy (DCM), and the mouse model of CVB3 myocarditis is routinely used to understand DCM pathogenesis. Mechanistically, autoimmunity is suspected due to the presence of autoantibodies for select antigens. However, their role continues to be enigmatic, which also raises the question of whether the breadth of autoantibodies is sufficiently characterized. Here, we attempted to comprehensively analyze the autoantibody repertoire using Phage ImmunoPrecipitation Sequencing (PhIP-Seq), a versatile and high-throughput platform, in the mouse model of CVB3 myocarditis. First, PhIP-Seq analysis using the VirScan library revealed antibody reactivity only to CVB3 in the infected group but not in controls, thus validating the technique in this model. Second, using the mouse peptide library, we detected autoantibodies to 32 peptides from 25 proteins in infected animals that are ubiquitously expressed and have not been previously reported. Third, by using ELISA as a secondary assay, we confirmed antibody reactivity in sera from CVB3-infected animals to cytochrome c oxidase assembly factor 4 homolog (COA4) and phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1), indicating the specificity of antibody detection by PhIP-Seq technology. Fourth, we noted similar antibody reactivity patterns in CVB3 and CVB4 infections, suggesting that the COA4- and PIK3AP1-reactive antibodies could be common to multiple CVB infections. The specificity of the autoantibodies was affirmed with influenza-infected animals that showed no reactivity to any of the antigens tested. Taken together, our data suggest that the autoantibodies identified by PhIP-Seq may have relevance to CVB pathogenesis, with a possibility that similar reactivity could be expected in human DCM patients.

Project description:The germ layer concept has been one of the foremost organizing principles in developmental biology, classification, systematics and evolution for 150 years. Of the three germ layers, the mesoderm is found in bilaterian animals but is absent in species in the phyla Cnidaria and Ctenophora, which has been taken as evidence that the mesoderm was the final germ layer to evolve. The origin of the ectoderm and endoderm layers, however, remains unclear with models supporting the antecedence of each as well as a simultaneous origin. We hypothesized that global analysis of gene expression in each layer throughout development may resolve the early events of animal evolution. Here, we determine the temporal and spatial components of gene expression spanning embryonic development for all C. elegans genes and use it to determine the evolutionary age of the germ layers. The gene expression programs of the mesoderm is generally induced after the ectoderm and endoderm germ layers, thus making it the last germ layer to both evolve and develop. Strikingly, the C. elegans endoderm and ectoderm expression programs do not co-induce; rather the endoderm activates earlier. We also observed early expression of endoderm orthologs during the embryology of Xenopus tropicalis, Nematostella vectensis, and the sponge Amphimedon queenslandica. Querying for the phylogenetic ages of specifically expressed genes revealed that the endoderm is comprised of older genes, supporting its antecedence among the germ layers. Taken together, we propose that the endoderm program has retained the feeding functions of the last common ancestor with the choanoflagellates, thus allowing for the specialization of an ectoderm germ layer. Our work reveals that the evolutionary appearance of the germ layers continues to constrain regulatory networks in metazoans. Two temporal assays of C. elegans embryonic development, starting at the zygote: (a) Embryos collected at fixed (~10 minute) time intervals. (b) Embryo segregates, up to five lines of blastomeres, isolated in reference to mitotic events. There were 184 samples in total, representing 100 distnict data points.

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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis.

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Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis.

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