TLR7 deficiency enhances inflammation in the URT but reduces LRT immunity following influenza A infection

Immune responses in the upper respiratory tract (URT) following influenza A virus (IAV) infection can influence disease severity, and subsequently inflammation and lung tissue damage in the lower respiratory tract (LRT). This study investigated the role of toll-like receptor 7 (TLR7), a key pattern recognition receptor that senses viral RNA and triggers antiviral and proinflammatory signaling to activate immune responses, in specifically shaping URT and LRT immune responses to IAV infection. Wild type C57Bl/6 and TLR7 knockout (TLR7 KO) mice were infected with the H3N2 IAV strain Hk-X31, and key immune responses in the nasal tissue (URT) and lower airways and lung tissue (LRT) measured after acute infection. We found reduced body weight loss, and increased type II/III interferons and proinflammatory cytokines in the URT of TLR7 KO mice; while LRT inflammation was reduced. TLR7 was essential for activating immune responses in the LRT but played a more selective role in the URT, primarily influencing monocytes, pDCs and B cells. Our data suggest that TLR7 plays a critical role in the transition of inflammation from the URT to the LRT during IAV infection, making it a promising therapeutic target to modulate disease severity.