School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
School of Veterinary Medicine, Veterinary Science Centre, University College Dublin, Dublin, Ireland.
Mucosal Immunol. 2015 Sep;8(5):982-92. doi: 10.1038/mi.2014.125. Epub 2014 Dec 17.
Bordetella pertussis causes whooping cough, an infectious disease of the respiratory tract that is re-emerging despite high vaccine coverage. Here we examined the role of Toll-like receptor (TLR) adapter protein Mal in the control of B. pertussis infection in the lungs. We found that B. pertussis bacterial load in the lungs of Mal-defective (Mal(-/-)) mice exceeded that of wild-type (WT) mice by up to 100-fold and bacteria disseminated to the liver in Mal(-/-) mice and 50% of these mice died from the infection. Macrophages from Mal(-/-) mice were defective in an early burst of pro-inflammatory cytokine production and in their ability to kill or constrain intracellular growth of B. pertussis. Importantly, the B. pertussis bacterial load in the lungs inversely correlated with the number of alveolar macrophages. Despite the maintenance and expansion of other cell populations, alveolar macrophages were completely depleted from the lungs of infected Mal(-/-) mice, but not from infected WT mice. Our findings define for the first time a role for a microbial pattern-recognition pathway in the survival of alveolar macrophages and uncover a mechanism of macrophage-mediated immunity to B. pertussis in which Mal controls intracellular survival and dissemination of bacteria from the lungs.
百日咳博德特氏菌引起百日咳，这是一种呼吸道传染病，尽管疫苗接种率很高，但仍在重新出现。在这里，我们研究了 Toll 样受体（TLR）衔接蛋白 Mal 在控制肺部百日咳博德特氏菌感染中的作用。我们发现，Mal 缺陷型（Mal(-/-)）小鼠肺部的百日咳博德特氏菌载量比野生型（WT）小鼠高 100 倍以上，细菌扩散到肝脏，这些小鼠中有 50%死于感染。Mal(-/-)小鼠的巨噬细胞在早期促炎细胞因子产生和杀死或限制百日咳博德特氏菌的能力方面存在缺陷。重要的是，肺部的百日咳博德特氏菌载量与肺泡巨噬细胞的数量呈反比。尽管维持和扩大了其他细胞群体，但感染 Mal(-/-)小鼠的肺部完全耗尽了肺泡巨噬细胞，但感染 WT 小鼠的肺部没有耗尽。我们的研究结果首次定义了微生物模式识别途径在肺泡巨噬细胞存活中的作用，并揭示了 Mal 控制细菌从肺部的细胞内存活和传播的机制，这是一种百日咳博德特氏菌的巨噬细胞介导免疫机制。
