Knapp Sylvia, Wieland Catharina W, Florquin Sandrine, Pantophlet Ralph, Dijkshoorn Lenie, Tshimbalanga Ntambua, Akira Shizuo, van der Poll Tom
Laboratory of Experimental Internal Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, G2-132, 1105 AZ Amsterdam, The Netherlands.
Am J Respir Crit Care Med. 2006 Jan 1;173(1):122-9. doi: 10.1164/rccm.200505-730OC. Epub 2005 Oct 6.
Acinetobacter baumannii is an opportunistic bacterial pathogen that is increasingly associated with gram-negative nosocomial pneumonia, but the molecular mechanisms that play a role in innate defenses during A. baumannii infection have not been elucidated.
To gain first insight into the role of CD14 and Toll-like receptors 4 and 2 in host response to A. baumannii pneumonia.
Respective gene-deficient mice were intranasally infected with A. baumannii, and bacterial outgrowth, lung inflammation, and pulmonary cytokine/chemokine responses were determined. To study the importance of LPS in the inflammatory response, mice were also challenged with A. baumannii LPS.
Bacterial counts were increased in CD14 and Toll-like receptor 4 gene-deficient mice, and only these animals developed bacteremia. The pulmonary cytokine/chemokine response was impaired in Toll-like receptor 4 knockout mice and the onset of lung inflammation was delayed. In contrast, Toll-like receptor 2-deficient animals displayed an earlier cell influx into lungs combined with increased macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 concentrations, which was associated with accelerated elimination of bacteria from the pulmonary compartment. Neither CD14 nor Toll-like receptor 4 gene-deficient mice responded to intranasal administration of LPS, whereas Toll-like receptor 2 knockout mice were indistinguishable from wild-type animals.
Our results suggest that CD14 and Toll-like receptor 4 play a key role in innate sensing of A. baumannii via the LPS moiety, resulting in effective elimination of the bacteria from the lung, whereas Toll-like receptor 2 signaling seems to counteract the robustness of innate responses during acute A. baumannii pneumonia.
鲍曼不动杆菌是一种机会性细菌病原体，越来越多地与革兰氏阴性医院获得性肺炎相关，但在鲍曼不动杆菌感染期间参与固有防御的分子机制尚未阐明。
初步了解CD14、Toll样受体4和2在宿主对鲍曼不动杆菌肺炎反应中的作用。
分别用鲍曼不动杆菌经鼻感染基因缺陷小鼠，测定细菌生长、肺部炎症和肺细胞因子/趋化因子反应。为研究脂多糖（LPS）在炎症反应中的重要性，还用鲍曼不动杆菌LPS对小鼠进行攻击。
CD14和Toll样受体4基因缺陷小鼠的细菌计数增加，只有这些动物发生了菌血症。Toll样受体4基因敲除小鼠的肺细胞因子/趋化因子反应受损，肺部炎症的发作延迟。相比之下，Toll样受体2缺陷动物肺部细胞流入更早，同时巨噬细胞炎性蛋白-2和单核细胞趋化蛋白-1浓度增加，这与肺部细菌的加速清除有关。CD14和Toll样受体4基因缺陷小鼠对鼻内给予LPS均无反应，而Toll样受体2基因敲除小鼠与野生型动物无差异。
我们的结果表明，CD14和Toll样受体4通过LPS部分在鲍曼不动杆菌的固有感知中起关键作用，从而有效地从肺部清除细菌，而Toll样受体2信号似乎在急性鲍曼不动杆菌肺炎期间抵消了固有反应的强度。
