Toll-like receptor 5 Agonist Improves the Therapeutic Efficacy of Antibiotic Treatments of Primary and Post-influenza Pneumococcal Infections

Antibiotics are widely recognized as an effective medical intervention against bacterial infections. However, antibiotic resistance increases while development of new antibiotics dries out. Previous reports showed that stimulation of innate immunity through intranasal administration of flagellin, the agonist for the Toll-like receptor 5 (TLR5), promote the clearance of pathogenic bacteria in pneumonia models. We hypothesized that a TLR5-mediated stimulation of lung immunity could improve the therapeutic index of antibiotics to cure Streptococcus pneumoniae respiratory infection in mice. Treatments were performed by combining intranasal administrations of flagellin with either oral regimen of amoxicillin or systemic injection of co-trimoxazole. Compared to standalone treatments, the combination of antibiotic and flagellin increased the survival rate and reduced the bacterial load in lung and spleen. As observed in antibiotic therapy, combinatory treatments improved lung architecture of infected animals but did not induce any inflammation. Moreover, combinatory treatment was also more effective than standalone antibiotic treatment in post-influenza pneumococcal infection. Finally, TLR5 signaling was shown mandatory for the effectiveness of therapy. Therefore, this study represents the first evidence that treatment combining antibiotic and a TLR agonist can improve the course of respiratory infections, thereby representing a new antibacterial strategy.