Pathogenesis of Klebsiells airway infections

描述(由申请人提供)：肺炎克雷伯氏菌是一种机会性病原体，可导致大量患者的肺部感染。抗生素耐药菌株的普遍存在，特别是那些产生超广谱β-内酰胺酶的菌株，在住院个人和慢性酗酒者等群体中是一个严重的临床问题。克雷伯氏菌呼吸道感染的发病机制尚未得到很大程度的研究，毒力决定因素的产生主要集中在胶囊作为抗吞噬因子的作用上。小鼠已被广泛用作肺炎克雷伯菌引起的呼吸道感染的模型，主要用于研究宿主细胞的反应。此外，流行病学观察表明，特定的包膜血清型(如K2)最常与肺部感染有关。然而，我们的初步数据表明，在小鼠感染模型中，并不是所有的K2阳性分离物都是毒力的。因此，尽管胶囊最有可能是一种抗吞噬因子，并防止在体内有效地杀死细菌，但其他因素是必要的，以建立呼吸道感染和随后的血液入侵。我们建议确定和确认以前未知的毒力因子在介导肺炎克雷伯菌引起的呼吸道感染中的作用。三种技术：签名标记突变、消减杂交和体内基因表达技术将识别这些决定因素。克雷伯氏菌感染的小鼠模型将被用来证明假定的毒力因素在感染过程中的作用。这三种方法是互补的，已被用于研究许多不同类型病原体的毒力。由于对肺炎克雷伯菌的毒力因子知之甚少，预计这些研究将提供有关这些细菌产生的新的和新的毒力因子的信息。对机会性感染设计新的治疗方法的基础将是了解这组生物体产生的毒力因素。

DESCRIPTION (provided by applicant): The opportunistic pathogen, Klebsiella pneumoniae, is responsible for a significant number of pulmonary infections in compromised individuals. The ubiquity of antibiotic resistant strains, particularly those producing extended-spectrum beta-lactamases, presents a serious clinical problem among groups such as hospitalized individuals and chronic alcoholics. The pathogenesis of Klebsiella airway infections has not been studied to any great extent and the investigation of the production of virulence determinants has essentially focused upon the role of capsules as antiphagocytic factors. The mouse has been extensively used as a model of airway infections due to K. pneumoniae primarily to investigate host cell responses. Also, epidemiologic observations suggest that specific capsular serotypes (e.g. K2) are most frequently associated with pulmonary infections. However, our preliminary data indicate that not all K2-positive isolates are virulent in the mouse model of infection. Therefore, although the capsule is most likely to be an antiphagocytic factor and prevent efficient killing of the bacteria in vivo, additional factors are necessary to establish airway infections with subsequent invasion of the bloodstream. We propose to identify and confirm the role of previously unknown virulence factors that mediate airway infections due to K. pneumoniae. Three techniques; signature-tagged mutagenesis, subtractive hybridization and in vivo gene expression technology will identify these determinants. The murine model of Klebsiella infection will be used to demonstrate the role of putative virulence factors during infection. The three approaches are complementary and have been used to investigate virulence in many different types of pathogens. Since very little is known about the virulence factors of K. pneumoniae, it is anticipated that these studies will provide information on new and novel virulence factors produced by these bacteria. Fundamental to devising new therapeutic approaches to opportunistic infections will be an understanding of the virulence factors produced by this group of organisms.