Firoved Aaron M, Ornatowski Wojciech, Deretic Vojo
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM 87131, USA.
Infect Immun. 2004 Sep;72(9):5012-8. doi: 10.1128/IAI.72.9.5012-5018.2004.
The main cause of the high morbidity and mortality of cystic fibrosis (CF) is the progressive lung inflammation associated with Pseudomonas aeruginosa colonization. During the course of chronic CF infections, P. aeruginosa undergoes a conversion to a mucoid phenotype. The emergence of mucoid P. aeruginosa in CF is associated with increased inflammation, respiratory decline, and a poor prognosis. Here we show, by the use of microarray analysis, that upon P. aeruginosa conversion to mucoidy, there is a massive and preferential induction of genes encoding bacterial lipoproteins. Bacterial lipoproteins are potent agonists of Toll-like receptor 2 (TLR2) signaling. The expression of TLR2 in human respiratory epithelial cells was ascertained by Western blot analysis. Human respiratory epithelial cells responded in a TLR2-dependent manner to bacterial lipopeptides derived from Pseudomonas lipoproteins induced in mucoid strains. The TLR2 proinflammatory response was further augmented in CF cells. Thus, the excessive inflammation in CF is the result of a global induction in mucoid P. aeruginosa of lipoproteins that act as proinflammatory toxins (here termed lipotoxins) superimposed on the hyperexcitability of CF cells. Blocking the signaling cascade responding to bacterial lipotoxins may provide therapeutic benefits for CF patients.
囊性纤维化(CF)高发病率和高死亡率的主要原因是与铜绿假单胞菌定植相关的进行性肺部炎症。在慢性CF感染过程中,铜绿假单胞菌会转变为黏液样表型。CF中黏液样铜绿假单胞菌的出现与炎症加剧、呼吸功能下降及预后不良有关。在此我们通过微阵列分析表明,当铜绿假单胞菌转变为黏液样时,编码细菌脂蛋白的基因会大量且优先被诱导。细菌脂蛋白是Toll样受体2(TLR2)信号传导的有效激动剂。通过蛋白质印迹分析确定了人呼吸道上皮细胞中TLR2的表达。人呼吸道上皮细胞以TLR2依赖的方式对黏液样菌株中诱导产生的源自铜绿假单胞菌脂蛋白的细菌脂肽作出反应。CF细胞中的TLR2促炎反应进一步增强。因此,CF中的过度炎症是黏液样铜绿假单胞菌中作为促炎毒素(此处称为脂毒素)的脂蛋白整体诱导叠加在CF细胞的过度兴奋性之上的结果。阻断对细菌脂毒素作出反应的信号级联反应可能会给CF患者带来治疗益处。