Transcriptional decoupling of the epithelial-immune bridge is associated with suboptimal influenza B virus immunogenicity.
TL;DR
This ex vivo primary ferret nasal epithelial cell and peripheral blood mononuclear cell co-culture model shows that signaling decoupling across the "epithelial-immune bridge" drives suboptimal IBV immunogenicity.
Abstract
Influenza B viruses (IBV) elicit weaker, less durable antibody responses than influenza A viruses (IAV) in ferrets. Using an ex vivo primary ferret nasal epithelial cell (FNEC) and peripheral blood mononuclear cell (PBMC) co-culture model, we demonstrate that this deficit is not caused by poor viral fitness. IAV and IBV replicate to equivalent apical titers (p = 0.190) and trigger equivalent basolateral interferon lambda (IFNλ) protein (p > 0.98) and induction of RIG-I, IFNλ3, and TSLP (p > 0.83) at 48 h post-infection (hpi). However, subsequent downstream signaling in recruited PBMC diverges. At 48 hpi, IBV induces uncoupled signaling featuring 1160.1-fold TYK2 induction (p = 0.032). By 72 hpi, IAV maintains pro-inflammatory output, whereas IBV shifts toward a regulatory phase marked by GZMA (3.24-fold; p = 0.001), STAT3 (7.59-fold, p = 0.003) and TGFß (3.97-fold, p = 0.003). Spearman's analysis confirms the TYK2 vs. CCL5 axis is decoupled during IBV infection (rs = 0.5, p = 0.450) compared to robust coupling in IAV (rs = 0.89, p = 0.033). This signaling decoupling across the "epithelial-immune bridge" drives suboptimal IBV immunogenicity.
