PDF(Pubmed)
Abstract：
The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.
摘要：
COVID-19大流行是一种持续的全球健康威胁，然而，我们对这种疾病早期细胞反应动力学的理解仍然有限。在我们的SARS-CoV-2人类挑战研究中，我们使用鼻咽拭子和血液的单细胞多组学分析来暂时解决流产，血清阴性个体受到前AlphaSARS-CoV-2挑战的短暂和持续感染。我们的分析显示，上皮细胞和免疫细胞中细胞类型比例的快速变化以及与特定时间点和感染状态相关的数十种高度动态的细胞反应状态。我们观察到血液中的干扰素反应先于鼻咽反应。此外，鼻咽部免疫浸润早期发生在仅有短暂感染的个体的样本中,晚期发生在有持续感染的个体的样本中.接种前HLA-DQA2的高表达与预防持续感染有关。纤毛细胞表现出多种免疫反应，并且最允许病毒复制，而鼻咽T细胞和巨噬细胞感染则不有效。我们解决了54个T细胞状态，包括在携带会聚的SARS-CoV-2基序时克隆扩增的急性活化T细胞。我们新的计算管道Cell2TCR基于基因表达签名识别激活的抗原响应T细胞，并将其聚类为克隆型组和基序。总的来说,我们详细的时间序列数据可以作为Rosetta结石上皮和免疫细胞反应的指标,并揭示与感染防护相关的早期动态反应.
