Primary nasal influenza infection rewires tissue-scale memory response dynamics

Area of Science:

• Immunology
• Respiratory Medicine
• Single-cell Genomics

Background:

• The nasal mucosa is a primary site for respiratory viral infections.
• Understanding immune responses in the nasal mucosa is crucial for developing effective vaccines and therapeutics.

Purpose of the Study:

• To create a single-cell RNA-sequencing atlas of the murine nasal mucosa during primary and secondary influenza infection.
• To characterize cellular and molecular changes in the nasal mucosa following viral challenge.

Main Methods:

• Single-cell RNA sequencing of murine nasal mucosa across three regions during primary and rechallenge influenza infection.
• Compositional analysis, proportionality analysis, cell-cell communication inference, and microscopy.

Main Results:

• Influenza infection was restricted to the respiratory mucosa with distinct changes in immune and epithelial cell populations.
• A novel subset of Krt13+ nasal immune-interacting floor epithelial (KNIIFE) cells was identified, increasing alongside tissue-resident memory T (T_RM)-like cells.
• The CXCL16-CXCR6 axis was identified as a key communication pathway between KNIIFE and T_RM cells.
• Secondary influenza challenge elicited rapid, coordinated myeloid and lymphoid responses without epithelial proliferation.

Conclusions:

• The generated atlas provides a valuable reference for studying upper respiratory tract viral infections.
• Local, coordinated memory responses in the nasal mucosa are effective against secondary influenza challenge.
• The identification of KNIIFE cells and their interaction with T_RM cells opens new avenues for therapeutic and vaccine development.