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

Area of Science:

• Immunology
• Infectious Diseases
• Pharmacology

Background:

• Secondary bacterial pneumonia frequently complicates influenza infections, leading to increased mortality.
• Staphylococcus aureus coinfection poses a significant threat following influenza virus infection.

Purpose of the Study:

• To investigate the therapeutic potential of toll-like receptor 7 (TLR7) inhibition in combating influenza-associated Staphylococcus aureus coinfection.
• To evaluate the efficacy of the TLR7 antagonist IRS661 in a murine model of coinfection.

Main Methods:

• Murine model of influenza virus (PR8) and Staphylococcus aureus coinfection.
• Assessment of survival rates, pulmonary damage markers (total protein, LDH, ALT, urea nitrogen), and inflammatory infiltration.
• Ex vivo and in vivo analysis of macrophage function (phagocytosis, bactericidal activity, ROS production).
• Measurement of cytokine levels (IL-6, IL-1β, TNF-α, IFN-γ) and JNK phosphorylation.
• Transcriptomic analysis to identify modulated cellular pathways.

Main Results:

• TLR7 deficiency and IRS661 treatment significantly improved survival and reduced pulmonary damage in coinfected mice.
• Interventions maintained inflammatory infiltration and enhanced macrophage phagocytosis, bactericidal activity, and ROS production.
• IRS661 treatment led to reduced pro-inflammatory cytokines and increased IFN-γ, correlated with decreased JNK phosphorylation.
• Transcriptomic analysis revealed IRS661 modulated pathways related to cell adhesion, metabolism, and oxidative stress.

Conclusions:

• TLR7 antagonism, particularly with IRS661, demonstrates significant therapeutic promise for influenza-associated secondary bacterial infections.
• IRS661 enhances innate immune responses against Staphylococcus aureus, offering a potential clinical translation strategy.