Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

Area of Science:

• Immunology
• Virology
• Genomics

Background:

• The COVID-19 pandemic highlights gaps in understanding early cellular immunity to SARS-CoV-2.
• Limited knowledge exists on the temporal dynamics of host responses during initial infection stages.

Purpose of the Study:

• To temporally resolve abortive, transient, and sustained SARS-CoV-2 infections using single-cell multi-omics.
• To identify dynamic cellular responses in epithelial and immune cells during early infection.
• To investigate early immune responses associated with protection against sustained infection.

Main Methods:

• Single-cell multi-omics profiling of nasopharyngeal swabs and blood from seronegative individuals challenged with SARS-CoV-2.
• Temporal analysis of cell-type proportions and cellular response states.
• Development and application of the Cell2TCR computational pipeline to identify antigen-responding T-cells.

Main Results:

• Rapid changes in cell-type proportions and dynamic cellular responses were observed.
• Interferon response in blood preceded nasopharyngeal response.
• Early nasopharyngeal immune infiltration correlated with transient infection; later infiltration with sustained infection.
• High HLA-DQA2 expression pre-inoculation was linked to protection against sustained infection.
• Ciliated cells showed high permissiveness to viral replication, while T-cells and macrophages exhibited non-productive infection.
• 54 T-cell states were identified, including clonally expanded T-cells with convergent SARS-CoV-2 motifs.

Conclusions:

• Detailed time-series data provide a comprehensive view of epithelial and immune cell responses to SARS-CoV-2.
• Early dynamic immune responses are associated with protection against sustained infection.
• The Cell2TCR pipeline aids in identifying and clustering antigen-responding T-cells.