TLR7 Deficiency Reveals Compartment-Specific Respiratory–Systemic Immune Responses During Severe Influenza A Virus Infection

Influenza A virus (IAV) infection can progress from a localized respiratory illness to severe disease characterized by pulmonary inflammation, systemic cytokinemia, acute-phase responses and multi-organ pathology. Toll-like receptor 7 (TLR7) is a key sensor of viral single-stranded RNA and an important component of antiviral immunity; however, its role in extending immunity from the respiratory tract to peripheral compartments during severe IAV infection remains incompletely understood. Here, we investigated the relationship between TLR7 and innate, cellular and humoral immune responses across respiratory and peripheral compartments during IAV infection. Using TLR7-deficient mice infected with the highly pathogenic PR8 H1N1 strain, we profiled immune responses in nasal tissue, bronchoalveolar lavage fluid, lung, blood and spleen, together with cytokine production, C-reactive protein levels, T cell activation and antibody isotype responses. Loss of TLR7 was accompanied by compartment-specific alterations in innate immunity, including differences in pulmonary macrophage and dendritic cell responses, and altered plasmacytoid dendritic cell distribution across respiratory and peripheral compartments. Reduced virus-specific CD8+ T cell expansion, lower IFNγ and TNFα production by T cells, and diminished circulating inflammatory cytokines and C-reactive protein were also observed. In parallel, altered humoral responses included reduced mucosal IgA, systemic IgM and Th1-associated IgG2a responses, together with changes in antibody isotype distribution. Collectively, these findings demonstrate that TLR7 deficiency is associated with broad, compartment-specific alterations in innate and adaptive immune responses during established IAV infection, extending across the respiratory tract, blood and spleen and correlating with disease severity. These findings support a role for TLR7-associated signaling in shaping the broader respiratory–systemic immune response, with its presence linked to both antiviral immune engagement and the magnitude of systemic inflammation during severe IAV infection.