Comparative Toll-Like Receptor 4-Mediated Innate Host Defense toBordetellaInfection

Abstract

Bordetella pertussis,B. parapertussis, andB. bronchisepticaare closely related species associated with respiratory disease in humans and other mammals. WhileB. bronchisepticahas a wide host range,B. pertussisandB. parapertussisevolved separately from aB. bronchiseptica-like progenitor to naturally infect only humans. Despite very different doubling times in vitro, all three establish similar levels of infection in the mouse lung within 72 h. Recent work has revealed separate roles for Toll-like receptor 4 (TLR4) in immunity toB. pertussisandB. bronchiseptica, while no role for TLR4 duringB. parapertussisinfection has been described. Here we compared the requirement for TLR4 in innate host defense to these organisms using the same mouse infection model. WhileB. bronchisepticacauses lethal disease in TLR4-deficient mice,B. pertussisandB. parapertussisdo not. Correspondingly, TLR4 is critical in limitingB. bronchisepticabut notB. pertussisorB. parapertussisbacterial numbers during the first 72 h. Interestingly,B. bronchisepticainduces a TLR4-dependent cytokine response that is considerably larger than that induced byB. pertussisorB. parapertussis. Analysis of their endotoxins using RAW cells suggests thatB. bronchisepticalipopolysaccharide (LPS) is 10- and 100-fold more stimulatory thanB. pertussisorB. parapertussisLPS, respectively. The difference in LPS stimulus is more pronounced when using HEK293 cells expressing human TLR4. Thus, it appears that in adapting to infect humans,B. pertussisandB. parapertussisindependently modified their LPS to reduce TLR4-mediated responses, which may compensate for slower growth rates and facilitate host colonization.