Restriction liée à l'âge de l'infection par l'adénovirus dans l'épithélium bronchique primaire

Adenoviruses are respiratory viruses that primarily infect the upper airways and usually cause mild symptoms such as the common cold, largely controlled by life-long immunity established after childhood infections. However, certain genotypes are linked to more severe respiratory disease accompanied by proinflammatory cytokine release. This thesis aims to understand how adenoviruses spread in bronchial epithelia (BE), the intrinsic mechanisms regulating this process, and how viral infections can induce cross-protection against other respiratory viruses. We established a model of primary BE grown at the air–liquid interface from lung brushes of healthy adult and pediatric donors. Using C-type adenoviruses (CAR receptor) and B-type adenoviruses (DSG2 receptor), we tracked viral spread with genetically tagged strains and clinical isolates through live imaging and confocal microscopy. Epithelial integrity and apical/basolateral viral release were monitored to characterize infection dynamics. To define epithelial responses, we analyzed transcriptional changes at peak infection using scRNA-seq. Adenovirus infection progressed from local foci that developed into macroscopic lesions, coinciding with a decline in transepithelial electrical resistance, indicating loss of integrity. Spread occurred first apically, then basolaterally after epithelial damage. No major differences were found between BEs from adult and pediatric donors. Our data suggest a model where local foci gradually compromise epithelial integrity, allowing trans-epithelial spread. At the transcriptional level, infection induced a distinct cell subpopulation with upregulated FAM111B, a putative restriction factor. Single-cell RNA-seq further revealed enhanced interferon signaling and strong induction of interferon-stimulated genes (ISGs).We therefore investigated whether virus-induced interferon responses confer cross-protection against other respiratory viruses. BEs from both donor groups were infected with three common respiratory viruses differing in genome type, replication strategy, and innate immune kinetics: adenovirus, rhinovirus A (RVA), and rhinovirus C (RVC). We compared replication dynamics, innate immune responses, and infection morphology, and profiled transcriptional responses to RVA and RVC at peak infection using scRNA-seq. To test cross-protection, BEs pre-infected with each virus were challenged with GFP-expressing RVA, and infection was quantified after 24 hours.All three viruses induced cross-protection, though with distinct kinetics. Adenovirus showed delayed infection dynamics, leading to correspondingly delayed immune responses. Bulk RNA-seq of cross-protected vs. non-protected BEs identified a distinct ISG signature associated with epithelial cross-protection, including IFI44L, one of the strongest correlates, whose antiviral function remains poorly defined.These findings highlight how adenovirus infections spread and alter epithelial responses, demonstrate the ability of respiratory viruses to induce cross-protection, and identify ISGs—particularly IFI44L—as potential key mediators. This opens perspectives for future studies to dissect the antiviral role of IFI44L and evaluate its potential as a therapeutic target to enhance antiviral immunity in the respiratory tract.