REGULATORY FUNCTIONS OF IRF3 IN PULMONARY BURKHOLDERIA THAILANDENSIS INFECTION

Abstract

Melioidosis is caused by Burkholderia pseudomallei (Bp) and high mortality rate is a cause of concern in the tropics. With absence of vaccines and emergence of antibiotic resistant strains, a better understanding of host innate immunity during Bp infection may facilitate development of novel therapies. IRF3 regulates antiviral type I IFN production but its role in bacterial infection remains relatively unclear. Therefore, we examined IRF3’s role during Burkholderia infection. IRF3 differentially modulated key innate immune cells. In macrophages, IRF3 suppressed Bt-uptake, triggered apoptosis and reduced C1-inflammasome activation. While in neutrophils, IRF3 dampened bactericidal mechanisms and partook in neutrophil extracellular traps formation. Independent of its type I IFN activity, IRF3 was found to be detrimental in a lethal murine melioidosis model, where Irf3-/- mice survived the challenge, had lower bacterial burden and milder inflammation than infected WT mice. Therefore, targeting IRF3 may serve as a potential therapeutic strategy against Bp infection.