Genetics & Biology of M. catarrhalis LOS in Otitis Media

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。一个重要的细菌表面成分被认为是一个潜在的毒力因子，就是脂寡糖(LOS)。结构研究表明，卡他毛杆菌LOS与其他革兰氏阴性人类病原体的LOS相似，包括脑膜炎奈瑟菌、淋球菌和流感嗜血杆菌。更重要的是，卡氏支原体共有的这些共同的LOS结构和这些突出的人类粘膜病原体被认为是毒力因子。虽然卡他毛虫表达这些LOS表位，但描述LOS在发病机制中的作用的研究很少。此外，目前还没有关于这种主要表面糖脂的组装和表达的信息。在这项提案中，我们将对卡氏微囊藻的遗传学和生物学进行全面的分析。这些研究将有助于我们理解LOS在中耳炎发病机制中的作用，并将为预防这种疾病的新策略提供洞察力。我们将通过以下具体目标来验证我们的假设：(1)分离和鉴定参与卡他藻生物合成和组装的基因。(2)进行生物学研究以明确卡他分支杆菌在中耳炎中的作用。

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 b-lactamase. Together, these data have stimulated research efforts aimed at identifying specific virulence factors involved in colonization and infection. One prominent bacterial surface component implicated as a potential virulence factor, is the lipooligosaccharide (LOS). Structural studies show that M. catarrhalis LOS is similar to the LOS of other Gram-negative human pathogens, including Neisseris meningitidis, Neisseria gonorrhoeae and Haemophilus influenzae. More importantly, these common LOS structures shared by M. catarrhalis and these prominent human mucosal pathogens have been implicated as virulence factors. Although M. catarrhalis express these LOS epitopes, there have been minimal studies describing the role of LOS in pathogenesis. In addition, there is currently no information available regarding the assembly and expression of this major surface glycolipid. In this proposal we will perform a comprehensive analysis of the genetics and biology of M. catarrhalis LOS. These studies will be instrumental to our understanding of the role of LOS in the pathogenesis of otitis media and should provide insight into new strategies designed to prevent this disease. We will test our hypotheses by the following specific aims: (1) Isolate and characterize of the genes involved in the biosynthesis and assembly of M. catarrhalis LOS. (2)Perform biologic studies to define the role for M. catarrhalis LOS in otitis media.