M. catarrhalis pili: Role in Colonization-infection

描述(申请人提供)：卡他莫拉氏菌是一种革兰氏阴性的人类病原体，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。这种细菌是中耳炎的第三大病因，据估计，大约50%的儿童在出生后的头6个月就会被这种细菌定植。反复的急性中耳炎感染也变得普遍，导致潜在的听力损失以及随后的发育和学习问题，因为这些孩子到了学龄期。中耳感染非常常见，据估计，80%的3岁以下儿童至少会经历一次发作。与治疗中耳炎相关的医疗保健费用也很高，已确定卡特哈里分枝杆菌每年约有300万至400万人次到医生办公室就诊。这一估计被认为是保守的，现在超过90%的卡他毛杆菌临床分离株产生β-内酰胺酶。总而言之，这些数据刺激了旨在确定与殖民和感染有关的特定毒力因素的研究工作。在2000年由全国疾病控制和预防中心主办的中耳炎媒体讲习班上，小组强调需要作出更多的研究努力，以确定细菌定植因素和确定新的疫苗和治疗目标。在这项建议中，我们描述了与卡他毛杆菌的生物合成和组装有关的基因的鉴定和特征。迄今为止，作为假定的殖民因素，这些结构一直被完全忽视。我们在本申请中提供的数据表明，我们已经鉴定出多个卡他分支杆菌基因与其他重要的革兰氏阴性人类病原体所描述的IV型菌毛(TFP)系统的基因同源。我们的研究表明，菌毛的表达在遗传和表型水平上都是保守的。我们假设菌毛的表达是早期定植阶段的一个重要组成部分，因此这些结构可能是人类免疫反应的重要靶点。这项建议的具体目的是：1)分离和鉴定参与卡他毛杆菌生物合成、组装、挤出和收回的基因。2)探讨卡他毛支原体在定植和致病中的作用，以及对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.