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

Abstract

Bordetella pertussis, B. parapertussis, and B. bronchiseptica are closely related species associated with respiratory disease in humans and other mammals. While B. bronchiseptica has a wide host range, B. pertussis and B. parapertussis evolved separately from a B. 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 to B. pertussis and B. bronchiseptica, while no role for TLR4 during B. parapertussis infection has been described. Here we compared the requirement for TLR4 in innate host defense to these organisms using the same mouse infection model. While B. bronchiseptica causes lethal disease in TLR4-deficient mice, B. pertussis and B. parapertussis do not. Correspondingly, TLR4 is critical in limiting B. bronchiseptica but not B. pertussis or B. parapertussis bacterial numbers during the first 72 h. Interestingly, B. bronchiseptica induces a TLR4-dependent cytokine response that is considerably larger than that induced by B. pertussis or B. parapertussis. Analysis of their endotoxins using RAW cells suggests that B. bronchiseptica lipopolysaccharide (LPS) is 10-and 100-fold more stimulatory than B. pertussis or B. parapertussis LPS, 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. pertussis and B. parapertussis independently modified their LPS to reduce TLR4-mediated responses, which may compensate for slower growth rates and facilitate host colonization.

Lipopolysaccharides from Bordetella pertussis and Bordetella parapertussis Differently Modulate Human Dendritic Cell Functions Resulting in Divergent Prevalence of Th17-Polarized Responses

“…The results were consistent with our study hypothesis; in fact, E. coli LPS and B. parapertussis LPS activities were dramatically inhibited by the presence of the neutralizing anti-CD14 mAb, whereas B. pertussis LOS stimulation was unaltered. Differences in CD14 usage by Bordetella LPS may explain the apparent contrast between our findings and the results published by Mann and colleagues (42), who have reported that B. pertussis LOS is a more efficacious stimulator of TLR4-transfected HEK 293 cells compared with B. parapertussis LPS. However, the cell line used by Mann et al (42) did not express CD14, thus nullifying the contribution of B. parapertussis LPS distal O-chain to TLR4 signaling.…”

Pertussis Toxin Inhibits Early Chemokine Production To Delay Neutrophil Recruitment in Response toBordetella pertussisRespiratory Tract Infection in Mice

“…One of the main inducers of proinflammatory responses to gram-negative bacteria is LPS, which signals primarily through Toll-like receptor 4 (TLR4) and induces the production of inflammatory chemokines and cytokines. There is evidence from in vitro studies that PT can modulate LPS-induced signaling through TLR4 (50,51); however, data obtained by Mann et al indicate that TLR4 is not critical for limiting B. pertussis bacterial loads during the first 3 days of infection in mice (23). To investigate if PT acts as an inhibitor of neutrophil recruitment and chemokine gene expression in response to LPS in vivo, we inoculated groups of BALB/c mice intranasally with 1, 10, or 100 ng of E. coli LPS with or without 100 ng of PT.…”

Acellular pertussis vaccination facilitatesBordetella parapertussisinfection in a rodent model of bordetellosis

“…Importantly, no evidence to support competitive interactions between B. pertussis and B. parapertussis was found in either sham-or aP-vaccinated co-infected hosts ( figure 1a -d ). An aP vaccine-driven reduction in inflammatory cytokine responses (figure 2) as well as neutrophil recruitment to the lung in response to B. parapertussis infection (figure 3)-two key players in the clearance of this pathogen Mann et al 2005;Wolfe et al 2009)-correlated with delayed B. parapertussis clearance. In addition, antibody responses in vaccinated B. parapertussis-infected hosts, although robust, were likely to have reduced efficacy relative to non-vaccinated hosts owing to species differences in prominent surface molecules preventing immune crossprotection (Wolfe et al 2007;Zhang et al 2009a,b).…”

“…First, robust T H 1 inflammatory responses and neutrophil recruitment to the LRT are required for optimal anamnestic responses against B. parapertussis Mann et al 2005;Wolfe et al 2005Wolfe et al , 2009). Here, we show that aP vaccination skews the host immune response towards a T H 2 response (Barnard et al 1996;Ryan et al 1997) and it is likely that this lack of inflammatory help-reduced lung inflammatory responses and neutrophil recruitment-enables B. parapertussis to evade rapid antibody-mediated clearance in our study (Wolfe et al 2009).…”