Mann Paul B, Wolfe Daniel, Latz Eicke, Golenbock Douglas, Preston Andrew, Harvill Eric T
Pathobiology Graduate Program, Immunology Research Laboratories, Department of Veterinary Science, The Pennsylvania State University, University Park, PA 16802, USA.
Infect Immun. 2005 Dec;73(12):8144-52. doi: 10.1128/IAI.73.12.8144-8152.2005.
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.
百日咳博德特氏菌、副百日咳博德特氏菌和支气管败血博德特氏菌是与人类及其他哺乳动物呼吸道疾病相关的密切相关菌种。虽然支气管败血博德特氏菌具有广泛的宿主范围，但百日咳博德特氏菌和副百日咳博德特氏菌是从类似支气管败血博德特氏菌的祖先进化而来，自然感染仅人类。尽管它们在体外的倍增时间差异很大，但这三种菌在72小时内在小鼠肺中建立的感染水平相似。最近的研究揭示了Toll样受体4（TLR4）在抵抗百日咳博德特氏菌和支气管败血博德特氏菌免疫中的不同作用，而在副百日咳博德特氏菌感染期间TLR4的作用尚未见报道。在这里，我们使用相同的小鼠感染模型比较了天然宿主防御中对这些菌的TLR4需求。虽然支气管败血博德特氏菌在TLR4缺陷小鼠中会导致致命疾病，但百日咳博德特氏菌和副百日咳博德特氏菌则不会。相应地，TLR4在最初72小时内对于限制支气管败血博德特氏菌数量至关重要，但对百日咳博德特氏菌或副百日咳博德特氏菌数量并无此作用。有趣的是，支气管败血博德特氏菌诱导的TLR4依赖性细胞因子反应比百日咳博德特氏菌或副百日咳博德特氏菌诱导的反应大得多。使用RAW细胞对它们的内毒素进行分析表明，支气管败血博德特氏菌脂多糖（LPS）的刺激作用分别比百日咳博德特氏菌或副百日咳博德特氏菌LPS强10倍和100倍。当使用表达人TLR4的HEK293细胞时，LPS刺激的差异更为明显。因此，似乎在适应感染人类的过程中，百日咳博德特氏菌和副百日咳博德特氏菌独立地修饰了它们的LPS以减少TLR4介导的反应，这可能弥补了较慢的生长速度并促进了宿主定殖。
