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.

COVID-19 大流行是一种持续的全球健康威胁，但我们对这种疾病的早期细胞反应动态的了解仍然有限 ¹ 。在我们的 SARS-CoV-2 人类攻击研究中，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受到前 Alpha SARS-CoV-2 攻击的血清阴性个体的流产、短暂和持续感染。我们的分析揭示了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，鼻咽免疫浸润早期发生在仅短暂感染个体的样本中，而较晚发生在持续感染个体的样本中。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，最适合病毒复制，而鼻咽 T 细胞和巨噬细胞则受到非生产性感染。我们解析了 54 种 T 细胞状态，包括急性激活的 T 细胞，这些细胞在携带聚合 SARS-CoV-2 基序时进行克隆扩增。我们的新计算管道 Cell2TCR 根据基因表达特征识别激活的抗原反应 T 细胞，并将它们聚类成克隆型组和基序。总的来说，我们详细的时间序列数据可以作为上皮细胞和免疫细胞反应的罗塞塔石碑，并揭示与防止感染相关的早期动态反应。