Boosting Toll-like receptor 4 signaling enhances the therapeutic outcome of antibiotic therapy in pneumococcal pneumonia

The emergence and spread of antibiotic resistance emphasize the need for alternative treatment strategies against bacterial infections. Boosting the host innate immune defenses is not only readily deployable in most individuals but can also mobilize many different antibacterial effectors. The present study tested the hypothesis whereby stimulation of the innate immune receptor Toll-like receptor 4 (TLR4) can be combined with antibiotics in the treatment of invasive pneumonia. In a mouse model of Streptococcus pneumoniae infection, a single oral administration of low-dose amoxicillin (AMX) or the systemic delivery of monophosphoryl lipid A (MPLA, a clinically-approved TLR4 activator) rapidly decreased the bacterial load in lung and spleen, although this was not sufficient for long-term survival. In contrast, a single treatment with a combination of MPLA and AMX induced significant bacterial clearance with little to no regrowth over time, and was associated with longer survival. Upregulation of genes related to granulocyte infiltration in lung tissue and elevation of blood levels of pro-inflammatory cytokines was immediate and transient in MPLA-treated mice; this indicates activation of the innate immune system in a context of infection. Combination treatment was also associated with a well-preserved lung tissue architecture and more rapid recovery from inflammation - suggesting that immune activation by MPLA does not exacerbate pneumonia-induced damage. Plasma AMX levels peaked and fell rapidly following administration, whereas the downstream effects of MPLA extended beyond AMX clearance; these findings suggested a two-step effect. Our results demonstrated that leveraging host innate immunity increases the efficacy of antibiotic therapy in bacterial pneumonia.