インペリアルのヒトチャレンジ研究が、COVIDにかからない人がいる理由の説明に役立つ(Imperial’s human challenge study helps explain why some people don’t get COVID)

2024-06-19 インペリアル・カレッジ・ロンドン(ICL)

<関連情報>

• https://www.imperial.ac.uk/news/254273/imperials-human-challenge-study-helps-explain/
• https://www.nature.com/articles/s41586-024-07575-x

ヒトSARS-CoV-2チャレンジで明らかになった局所および全身反応ダイナミクス Human SARS-CoV-2 challenge uncovers local and systemic response dynamics

Rik G. H. Lindeboom,Kaylee B. Worlock,Lisa M. Dratva,Masahiro Yoshida,David Scobie,Helen R. Wagstaffe,Laura Richardson,Anna Wilbrey-Clark,Josephine L. Barnes,Lorenz Kretschmer,Krzysztof Polanski,Jessica Allen-Hyttinen,Puja Mehta,Dinithi Sumanaweera,Jacqueline M. Boccacino,Waradon Sungnak,Rasa Elmentaite,Ni Huang,Lira Mamanova,Rakesh Kapuge,Liam Bolt,Elena Prigmore,Ben Killingley,Mariya Kalinova,… Sarah A. Teichmann
Nature  Published:19 June 2024
DOI:https://doi.org/10.1038/s41586-024-07575-x

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.