Exploring the Contribution of TLR7 to Sex-Based Disparities in Respiratory Syncytial Virus (RSV)-Induced Inflammation and Immunity

TLR7 plays a key role in recognizing viral RNA to initiate an immune response. Sex-based differences in the severity of RSV respiratory infections have been noted, and this may be related to higher expression of X-linked toll-like receptor 7 (TLR7) in female immune cells. Indeed, TLR7 has been shown to influence sex differences in responses to other respiratory viruses; however, its role in RSV infection remains underexplored. We infected adult C57Bl/6 or TLR7 knockout mice with RSV and compared the specific lung immune responses between different sexes. Gene expression analysis revealed that infected female mice had elevated levels of type I and II interferons, proinflammatory cytokines, chemokines, and viral transcripts in their lungs compared to males. Additionally, females exhibited increased numbers of macrophages and higher antibody responses in the airways. Deletion of TLR7 diminished the sex differences in certain cytokine and antibody responses. Furthermore, ex vivo infection of male alveolar macrophages with RSV resulted in greater production of proinflammatory cytokines and viral transcripts than in female macrophages, suggesting inherent sex differences in macrophage responses. These findings provide new insights into the mechanisms underlying sex differences in RSV pathophysiology and suggest that TLR7 contributes to an enhanced inflammatory response in females.