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粘膜病原体，是婴儿和儿童中耳感染和鼻窦炎的重要原因，也是成人肺部疾病恶化的重要来源。它是中耳炎(OM)的第三大病因，卡他毛虫的定殖率很高，因为50%的儿童在出生后6个月内就会被定植。OM的发病率也很高，因为大约80%的3岁以下儿童至少会经历一次发作。此外，复发性急性OM很常见，当这些儿童达到学龄时，会导致听力障碍和发育/学习问题。OM是直接和间接保健费用的一个重要来源，卡特哈里分枝杆菌每年有300万至400万人次到医生办公室就诊。这被认为是低的，因为诊断困难，因为鼓室穿刺术并不常见。这些事实刺激了旨在确定致病机制中涉及的毒力因素的研究。被认为是毒力因子的重要表面成分之一是脂低聚糖(LOS)。结构分析证实卡他毛杆菌LOS与革兰氏阴性菌脑膜炎奈瑟菌、淋病奈瑟菌和流感嗜血杆菌LOS相似。更重要的是，这些常见的碳水化合物表位与毒力有关，即粘附性、生物膜形成和血清抗性。迄今为止，很少有人对卡他分支杆菌在疾病中的作用进行评估。在这一领域缺乏研究的最可能的原因是，没有数据描述参与卡他藻LOS的生物合成和组装的基因，也没有明确的突变体可以用来描述不同寡糖结构的重要性。在过去的一段时间里，我们在这方面取得了重大进展，识别了17个LOS基因，并构建了每个特定的突变体。此外，我们和我们的合作者一起提出了一个潜在的动物定植模型，这可能是进行卡他毛虫活体研究的关键。我们现在可以继续进行遗传学和生物学研究，以检验我们的假设，即卡他毛杆菌分离株组装的血清型LOS结构与发病直接相关。我们进一步假设，A型和B型LOS结构可能比C型LOS结构更有优势。我们将通过以下具体目标来验证我们的假设：(1)确定卡特氏支原体LOS组装和生物合成所涉及的顺序步骤；(2)确定卡氏支原体LOS结构在发病中的作用。 中耳感染在你们这些孩子中相当普遍。据估计，超过80%的5岁以下儿童将经历至少一种这些类型的感染。卡他莫拉氏菌是一种导致15%-20%的细菌性中耳感染的微生物。这产生了一个重大的卫生保健问题，人们对确定疫苗目标非常感兴趣。因此，研究可能作为疫苗抗原的细菌成分是至关重要的，例如脂寡糖是这项工作的重点。

DESCRIPTION (provided by applicant): Moraxella catarrhalis is a Gram-negative human mucosal pathogen, a significant cause of middle ear infections and sinusitis in infants and children and an important source of exacerbations in adults with lung disease. It is the third leading cause of otitis media (OM) and there is a high colonization rate with M. catarrhalis, as 50% of children will be colonized in the first 6 months of life. The incidence of OM is also high and as about 80% of all children under under 3 will experience at least one episode. In addition, recurrent acute OM is prevalent resulting in hearing impairment and developmental/learning problems as these children reach school age. OM is a significant source of direct and indirect health care costs and M. catarrhalis is responsible for 3 to 4 million physician office visits annually. This is considered low as diagnosis is difficult because tympanocentesis is uncommon. These facts have stimulated research aimed at identifying virulence factors involved in pathogenesis. One of the prominent surface components implicated as a virulence factor is the lipooligosaccharide (LOS). Structural analysis confirmed that M. catarrhalis LOS shares similarities with the LOS of Gram-negative human pathogens, i.e. Neisseria meningitidis, N. gonorrhoeae and Haemophilus influenzae. More importantly, these common carbohydrate epitopes are involved in virulence, i.e. adherence, biofilm formation and serum resistance. To date there has been little effort to evaluate the role of M. catarrhalis LOS in disease. The most likely reason for the lack of research in this area involves the fact that there was no data describing the genes involved in the biosynthesis and assembly of M. catarrhalis LOS and there were no defined mutants that could be used to delineate the importance of different oligosaccharide structures. We have made significant progress in this area over the previous period identifying 17 LOS genes and constructing each specific mutant. In addition, we have proposed a potential animal colonization model, together with our collaborators, which could be critical in performing in vivo studies with M. catarrhalis. We are now in a position to continue genetic and biologic studies designed to test our hypothesis that the serotype LOS structure assembled by M. catarrhalis isolates is directly related to pathogenesis. We further hypothesize that the serotype A and serotype B LOS structures may provide an advantage over the serotype C LOS structure. We will test our hypotheses by the following specific aims: (1) Determine the sequential steps involved in the assembly and biosynthesis of M. catarrhalis LOS and (2) Determine the role of M. catarrhalis LOS structures in pathogenesis. Middle ear infections are quite prevalent among you children. It is estimated that over 80% of children under the age of 5 will experience at least one of these types of infections. Moraxella catarrhalis is an organism that causes 15-20% of all bacterial middle ear infections. This generates a significant health care issue and there is significant interest in identifying vaccine targets. Therefore it is critically important to investigate bacterial components that could be vaccine antigen such as the lipooligosaccharides that are the focus of this work.