Detecting early host-influenza mucosal interactions.

Influenza causes significant morbidity and mortality in children worldwide, with a higher burden in low- and middle-income countries. Little is known about early host-pathogen mucosal interactions in the upper respiratory tract that influence the course of infection. While controlled human influenza challenge models can provide such insight, these are not feasible or ethical in paediatric populations, where the burden of disease is highest. Instead, we have used live attenuated influenza vaccine (LAIV) as a surrogate experimental challenge agent. LAIV infects nasal epithelial cells and parallels many aspects of wild-type influenza in the nasopharynx, as the attenuated phenotype relates primarily to an inability to replicate in the lower respiratory tract. Using data from a cohort of people immunised with LAIV, we have explored pre-challenge mucosal gene expression signatures that correlate with nasopharyngeal viral load of LAIV strains. We have identified several pathways enriched for genes that influence how well influenza viruses can replicate in the upper respiratory tract. While some pathways are consistent with current knowledge, others represent entirely novel discovery about host defences against influenza. We now wish to validate some target genes in vitro using 3D human epithelial cell models. Our approach of using an unbiased systems-level analysis from clinical samples for a discovery phase, followed by detailed validation in vitro, has the potential to make significant advances in understanding host-pathogen interactions at a mucosal level.