Targeting TLR7 reprograms macrophage function to attenuate influenza-associated Staphylococcus aureus coinfection.

Abstract

Secondary bacterial pneumonia is a common cause of influenza infection associated deaths. This study investigated the potential therapeutic role of inhibiting toll-like receptor 7 (TLR7) in influenza-associated Staphylococcus aureus (S.aureus) coinfection. Both TLR7 deficiency and TLR7 antagonist IRS661 treatment significantly improved survival in mice coinfected with influenza virus (PR8) and S.aureus while significantly reducing pulmonary damage as evidenced by decreased total protein (TP) and lactate dehydrogenase (LDH) levels in bronchoalveolar lavage fluid (BALF) and serum alanine aminotransferase (ALT) and urea nitrogen (UREA) levels. Notably, both interventions significantly maintained the accumulated inflammatory infiltration observed within 6 h post-coinfection, and up to 48 h. Mechanistically, IRS661 enhanced macrophage phagocytosis, bactericidal activity, and reactive oxygen species (ROS) production ex vivo and in vivo. This effect was correlated with reduced c-Jun N-terminal kinase (JNK) phosphorylation. Furthermore, during early infection, this modulation was accompanied by significantly reduced levels of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, but a concomitant increase in IFN-γ. Transcriptomic analysis revealed IRS661 modulated pathways involved in cell adhesion, metabolism, and oxidative stress response. These findings suggested that TLR7 antagonism, specifically through IRS661, represented a promising therapeutic strategy for influenza-associated secondary bacterial infections, paving further investigations into its clinical translation potential.