Evidence of SARS-CoV-2-Specific T-Cell-Mediated Myocarditis in a MIS-A Case

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.

[1]  D. Walt,et al.  Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. , 2021, The Journal of clinical investigation.

[2]  Daniel S. Chertow,et al.  SARS-CoV-2 infection of the oral cavity and saliva , 2021, Nature Medicine.

[3]  H. Bodur,et al.  Multiple system inflammatory syndrome associated with SARS-CoV-2 infection in an adult and an adolescent , 2021, Rheumatology International.

[4]  S. Mallal,et al.  Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases , 2021, Cell Reports Medicine.

[5]  V. Pascual,et al.  The immune roadmap for understanding multi-system inflammatory syndrome in children: opportunities and challenges , 2020, Nature Medicine.

[6]  R. Atmar,et al.  Inflammatory syndromes associated with SARS-CoV-2 infection: dysregulation of the immune response across the age spectrum. , 2020, The Journal of clinical investigation.

[7]  C. Newton-Cheh,et al.  Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection — United Kingdom and United States, March–August 2020 , 2020, MMWR. Morbidity and mortality weekly report.

[8]  G. Mansueto.  COVID-19: Brief check through the pathologist's eye (autopsy archive) , 2020, Pathology - Research and Practice.

[9]  K. Reilly,et al.  COVID-19-Associated Multisystem Inflammatory Syndrome in Children - United States, March-July 2020. , 2020 .

[10]  Jennifer N. Dines,et al.  A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2 , 2020, Research square.

[11]  U. Eriksson,et al.  Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy , 2019, Science.

[12]  L. Mestroni,et al.  Dilated Cardiomyopathy: Genetic Determinants and Mechanisms , 2017, Circulation research.

[13]  P. Bradley,et al.  Quantifiable predictive features define epitope-specific T cell receptor repertoires , 2017, Nature.

[14]  Alessandro Sette,et al.  Identifying specificity groups in the T cell receptor repertoire , 2017, Nature.

[15]  W. Lipkin,et al.  Virome Capture Sequencing Enables Sensitive Viral Diagnosis and Comprehensive Virome Analysis , 2015, mBio.

[16]  M. Aouni,et al.  Coxsackievirus B detection in cases of myocarditis, myopericarditis, pericarditis and dilated cardiomyopathy in hospitalized patients , 2014, Molecular medicine reports.

[17]  I. Pastan,et al.  Class II human leucocyte antigen DRB1*11 in hairy cell leukaemia patients with and without haemolytic uraemic syndrome , 2014, British journal of haematology.

[18]  N. Rose.  Learning from myocarditis: mimicry, chaos and black holes , 2014, F1000prime reports.

[19]  R. Emerson,et al.  Using synthetic templates to design an unbiased multiplex PCR assay , 2013, Nature Communications.

[20]  Zhengwei Zhu,et al.  CD-HIT: accelerated for clustering the next-generation sequencing data , 2012, Bioinform..

[21]  Steven L Salzberg,et al.  Fast gapped-read alignment with Bowtie 2 , 2012, Nature Methods.

[22]  Marcel Martin.  Cutadapt removes adapter sequences from high-throughput sequencing reads , 2011 .

[23]  M. Tenforde,et al.  Coming Into Focus , 2009 .

[24]  N. Sarvetnick,et al.  Pancreatic expression of interferon-γ protects mice from lethal coxsackievirus B3 infection and subsequent myocarditis , 2000, Nature Medicine.

[25]  N. Rose.  Viral damage or ‘molecular mimicry’—placing the blame in myocarditis , 2000, Nature Medicine.