Molecular Pathogenesis of Klebsiella Pneumoniae

描述（由申请人提供）：肺炎克雷伯菌是一种机会性病原体，经常与住院患者的呼吸道和尿路感染有关。此外，它是慢性酗酒者肺炎的主要原因，也与社区获得性肺炎有关。感染尤其难以治疗，因为大多数临床分离株对几种抗生素表现出耐药性，导致治疗失败。在人的呼吸道中，已经提出肺炎克雷伯菌可以作为生长在肺组织上的生物膜存在。这些细菌产生大量的酸性多糖胶囊，已被证明具有抗吞噬特性，胶囊被认为是一个重要的毒力因子。然而，对这些细菌产生的其他毒力决定因素知之甚少，这些决定因素使它们能够在受干扰的上皮组织上定植和生长，侵入血液并成功克服宿主的防御机制。在本提案中，我们描述的研究继续我们的调查肺炎克雷伯菌的分子发病机制。我们将使用涂有人类来源的细胞外基质的流过生物膜室来确定在这些生物表面形成生物膜的毛状类型和其他基因产物的作用。在补充研究中，将利用小鼠急性感染模型来检查假定的毒力因子在体内的作用。在许多其他致病菌中，毒力因子表达的遗传调控涉及一个复杂的调控网络或调控。我们在本提案中描述了两个系列的研究，以检查在影响细菌在体内引起感染和体外在人基质上生长的能力方面发挥重要作用的调节因子。这些调控基因的目标将被确定。此外，像许多其他肠道细菌一样，肺炎克雷伯菌具有产生几种不同类型的菌毛的能力。在任何细菌种类中，不同毛类型的协调生产尚未得到详细的研究。分离出至少两种类型的叶缘表达改变的突变将使我们能够开始描述叶缘调控的特征。综上所述，本研究的目的是阐明菌膜在肺炎克雷伯菌发病机制中的作用，研究影响毒力的调控途径，并确定生物膜生长过程中毒力基因的表达。公共卫生相关性：本项目调查肺炎克雷伯菌引起呼吸道感染的机制。这些细菌经常导致住院病人呼吸道感染，

DESCRIPTION (provided by applicant): Klebsiella pneumoniae is an opportunistic pathogen frequently implicated in respiratory and urinary tract infections of hospitalized patients. In addition, it is a leading cause of pneumonia in chronic alcoholics and has also been associated with community acquired pneumonia. Infections are particularly difficult to treat since most clinical isolates exhibit resistance to several antibiotics leading to treatment failure. In the human respiratory tract it has been suggested that K. pneumoniae can exist as a biofilm growing on lung tissue. These bacteria produce copious amounts of an acidic polysaccharide capsule that has been shown to possess antiphagocytic properties and the capsule is believed to be an important virulence factor. However, relatively little is known about other virulence determinants produced by these bacteria which allow them to colonize and grow on perturbed epithelial tissues, invade into the bloodstream and successfully overcome host defense mechanisms. In this proposal we describe studies to continue our investigations into the molecular pathogenetic mechanisms of K. pneumoniae. We will use flow-through biofilm chambers coated with human-derived extracellular matrices to determine the role of fimbrial types and other gene products in forming a biofilm on these biotic surfaces. In complementary studies a murine model of acute infection will be utilized to examine the role of putative virulence factors in vivo. In many other pathogenic bacteria the genetic regulation of virulence factor expression involves a complex regulatory network or regulon. We describe in this proposal two series of studies to examine regulators that play an important role in influencing the ability of the bacteria to cause infections in vivo and grow on human matrices in vitro. The targets of these regulatory genes will be determined. In addition, like many other enteric bacteria, K. pneumoniae posses the ability to produce several different types of fimbriae or pili. The coordinate production of distinct fimbrial types has not been investigated in detail in any bacterial species. The isolation of mutations that cause alteration in at least two types of fimbrial expression will allow us to begin to characterize the fimbrial regulon. In summary the aims of this proposal are to elucidate the role of fimbriae in K. pneumoniae pathogenesis, to investigate the regulatory pathways affecting virulence, and to define virulence gene expression during biofilm growth. PUBLIC HEALTH RELEVANCE: This project investigates mechanisms used by the bacterium Klebsiella pneumoniae to cause infections of the airways. These bacteria frequently cause airway infections in hospitalized patients,