Severe lower respiratory tract disease following influenza A virus (IAV) infection is characterized by excessive inflammation and lung tissue damage, and this can impair lung function. The effect of toll-like receptor 7 (TLR7), which detects viral RNA to initiate antiviral and proinflammatory responses to IAV, on lung function during peak infection and in the resolution phase is not fully understood. Using wild-type (WT) C57BL/6 and TLR7 knockout (TLR7 KO) mice, we found that IAV infection induced airway dysfunction in both genotypes, although in TLR7 KO mice, this dysfunction manifested later, did not affect lung tissue elastance and damping, and was associated with a different immune phenotype. A positive correlation was found between lung dysfunction and the infiltration of neutrophils and Ly6Clo patrolling monocytes at day 7 post-infection. Conversely, in TLR7 KO mice, eosinophil and CD8+ cytotoxic T cells were associated with airway hyperactivity at day 14. IL-5 expression was higher in the airways of IAV-infected TLR7 KO mice, suggesting an enhanced Th2 response due to TLR7 deficiency. This study highlights an underappreciated duality of TLR7 in IAV disease: promoting inflammation-driven lung dysfunction during the acute infection but suppressing eosinophilic and CD8+ T cell-dependent hyperresponsiveness during disease resolution.
Keywords: infection; inflammation; influenza A; lung function; toll-like receptor 7.