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1.
Mol Cells ; 45(10): 738-748, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-35904026

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed a serious threat to global public health. A novel vaccine made from messenger RNA (mRNA) has been developed and approved for use at an unprecedented pace. However, an increased risk of myocarditis has been reported after BNT162b2 mRNA vaccination due to unknown causes. In this study, we used single-cell RNA sequencing and single-cell T cell receptor sequencing analyses of peripheral blood mononuclear cells (PBMCs) to describe, for the first time, changes in the peripheral immune landscape of a patient who underwent myocarditis after BNT162b2 vaccination. The greatest changes were observed in the transcriptomic profile of monocytes in terms of the number of differentially expressed genes. When compared to the transcriptome of PBMCs from vaccinated individuals without complications, increased expression levels of IL7R were detected in multiple cell clusters. Overall, results from this study can help advance research into the pathogenesis of BNT162b2-induced myocarditis.


Assuntos
COVID-19 , Miocardite , Vacinas Virais , Vacina BNT162 , Humanos , Leucócitos Mononucleares , Miocardite/etiologia , RNA Mensageiro/genética , SARS-CoV-2/genética , Vacinas Sintéticas , Vacinas de mRNA
2.
Proc Natl Acad Sci U S A ; 113(50): 14390-14395, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27911820

RESUMO

The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA- and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid- or virus-triggered activation of IFN-ß production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1-TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubule-associated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA- or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling.


Assuntos
Antígenos CD/metabolismo , Butirofilinas/metabolismo , Dineínas/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Ativo do Núcleo Celular , Antígenos CD/genética , Butirofilinas/antagonistas & inibidores , Butirofilinas/genética , Linhagem Celular , DNA Viral/imunologia , Técnicas de Silenciamento de Genes , Células HEK293 , Células HeLa , Humanos , Imunidade Inata , Interferon Tipo I/biossíntese , Microtúbulos/metabolismo , Modelos Biológicos , Fosforilação , RNA Interferente Pequeno/genética , RNA Viral/imunologia , Transdução de Sinais
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