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Published on: November 3, 2014
Targeting TLR7 reprograms macrophage function to attenuate influenza-associated Staphylococcus aureus coinfection
Te Chen1, Jiayu Liu2, Renlin Yu3
1The Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; The Key Laboratory of Diagnostic Medicine Designated By the Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
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.
Insights
Inhibiting toll-like receptor 7 (TLR7) with IRS661 improves survival in mice with influenza and Staphylococcus aureus coinfection. This therapeutic strategy reduces lung damage and enhances immune responses against secondary bacterial infections.
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.
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