M. catarrhalis pili:Role in Colonization and Infection

描述（由申请方提供）：卡他莫拉菌是一种革兰氏阴性人类病原体，主要引起婴儿和儿童的中耳感染和鼻窦炎，以及成人的下呼吸道感染。这种微生物是中耳炎的第三大原因，据估计，大约50%的儿童在出生后的前6个月内会被这种细菌定殖。复发性急性中耳炎感染也变得普遍，导致潜在的听力损失和随后的发展和学习问题，因为这些儿童达到学龄。中耳炎非常常见，据估计，80%的3岁以下儿童至少会经历一次发作。还存在与中耳炎的治疗相关的显著的卫生保健成本，并且已经确定M.卡他病导致每年约300万到400万的医生门诊。这个估计被认为是保守的，因为超过90%的M。卡他临床分离株产生β-内酰胺酶。总之，这些数据刺激了旨在确定涉及定植和感染的特定毒力因子的研究工作。在2000年由NIDCD主办的中耳炎研讨会上，该小组强调需要进行更多的研究工作，致力于确定细菌定植因素和确定新的疫苗和治疗靶点。在这个提议中，我们描述了参与M的生物合成和组装的基因的鉴定和表征。卡他皮利。到目前为止，这些结构已被完全忽略了假定的殖民因素。我们在本申请中提出的数据表明，我们已经确定了多个M。卡他病基因，与其它重要的革兰氏阴性人类病原体中描述的IV型皮利（TFP）系统的基因具有同源性。我们的研究表明，皮利表达在遗传和表型水平上都是保守的。我们假设皮利的表达是一个重要的组成部分，在早期阶段的殖民化，因此这些结构可能是重要的目标，为人类的免疫反应。本研究的具体目标是：1）分离和鉴定与M.卡他皮利。2)评价M的功能。卡他皮利在定殖和发病机制中的作用，并表征对PilA和PilQ的抗体应答。

DESCRIPTION (provided by applicant): Moraxella catarrhalis is a Gram-negative human pathogen, which predominantly causes middle ear infections and sinusitis in infants and children, and lower respiratory tract infections in adults. This organism is the third leading cause of otitis media and it is estimated that approximately 50% of children will become colonized by this bacterium in the first 6 months of life. Recurrent acute otitis media infections have also become prevalent resulting in potential hearing loss and subsequent developmental and learning problems as these children reach school age. Middle ear infections are very common and it is estimated that 80% of children under the age of 3 will experience at least one episode. There are also significant health care costs associated with treatment for otitis media and it has been determined that M. catarrhalis is responsible for approximately 3 to 4 million physician office visits annually. This estimate is considered conservative now that over 90% of M. catarrhalis clinical isolates produce beta-lactamase. Together, these data have stimulated research efforts aimed at identifying specific virulence factors involved in colonization and infection. At the otitis media workshop sponsored by the NIDCD in 2000 the panel emphasized the need for more research efforts dedicated to the identification of bacterial colonization factors and the identification of new vaccine and treatment targets. In this proposal we describe the identification and characterization of the genes that are involved in the biosynthesis and assembly of M. catarrhalis pili. To date these structures have been totally ignored as putative colonization factors. The data we present in this application demonstrate that we have identified multiple M. catarrhalis genes with homology to genes of the type IV pili (TFP) systems described for other important gram-negative human pathogens. Our studies show that pili expression is conserved both at the genetic and phenotypic levels. We hypothesize that pili expression is an essential component in the early stages of colonization and thus these structures may be important targets for the human immune response. The specific aims of this proposal are: 1) Isolate and characterize the genes involved in the biosynthesis, assembly, extrusion and retraction of M. catarrhalis pili. 2) Evaluate the function of M. catarrhalis pili in colonization and pathogenesis and characterize the antibody response to PilA and PilQ.