Roy M-F, Larivière L, Wilkinson R, Tam M, Stevenson M M, Malo D
Department of Human Genetics, McGill University Health Center, Montréal, Québec, Canada.
Genes Immun. 2006 Jul;7(5):372-83. doi: 10.1038/sj.gene.6364309. Epub 2006 Jun 1.
The mouse response to Salmonella Typhimurium infection is partly controlled through detection of the bacterium lipopolysaccharide by the host pattern recognition receptor, Toll-like receptor 4 (Tlr4). Mice deficient in Tlr4 signaling are extremely susceptible to Salmonella infection with a 1,000-fold reduction in LD(50). In a previous study, we showed, using transgenic mice carrying one, three, six and >30 copies of Tlr4, that the level of expression of this gene influences the outcome of Salmonella infection, with a plateau effect starting at three copies. In the present study, we further investigate the impact of Tlr4 during Salmonella infection in mice expressing Tlr4 at slightly sub-normal, normal and slightly supra-normal levels by comparing host responses in mice carrying one, two and three copies of Tlr4 on the same genetic background. We describe in detail the in vivo host response to pathogenic Salmonella and show for the first time, in this narrow range of Tlr4 expression, an incremental protective effect against Salmonella due to improved control of bacterial growth in target organs and increased expression of important immune response genes in the spleen.
小鼠对鼠伤寒沙门氏菌感染的反应部分是通过宿主模式识别受体Toll样受体4（Tlr4）检测细菌脂多糖来控制的。Tlr4信号通路缺陷的小鼠对沙门氏菌感染极为敏感，其半数致死剂量（LD50）降低了1000倍。在先前的一项研究中，我们使用携带1、3、6和>30个Tlr4拷贝的转基因小鼠表明，该基因的表达水平会影响沙门氏菌感染的结果，从3个拷贝开始出现平台效应。在本研究中，我们通过比较相同遗传背景下携带1、2和3个Tlr4拷贝的小鼠的宿主反应，进一步研究了Tlr4在沙门氏菌感染期间对表达水平略低于正常、正常和略高于正常水平的小鼠的影响。我们详细描述了体内宿主对致病性沙门氏菌的反应，并首次表明，在这个较窄的Tlr4表达范围内，由于对靶器官中细菌生长的更好控制以及脾脏中重要免疫反应基因表达的增加，对沙门氏菌具有递增的保护作用。
