Genetics & Biology of M. catarrhalis LOS in Otitis Media

描述（由申请方提供）：卡他莫拉菌是一种革兰氏阴性人类粘膜病原体，是婴儿和儿童中耳感染和鼻窦炎的重要原因，也是成人肺部疾病加重的重要来源。它是中耳炎（OM）的第三大原因，并且存在高的M定植率。卡他炎，因为50%的儿童将在生命的前6个月内定植。OM的发病率也很高，大约80%的3岁以下儿童至少会经历一次发作。此外，当这些儿童达到学龄时，复发性急性OM很普遍，导致听力障碍和发育/学习问题。OM是直接和间接卫生保健费用的重要来源，M。卡他病每年导致3 - 4百万的医生门诊。这被认为是低诊断是困难的，因为鼓室穿刺术是罕见的。这些事实刺激了旨在确定致病机制中涉及的毒力因子的研究。与毒力因子有关的一个突出的表面组分是脂寡糖（LOS）。结构分析证实M.卡他菌LOS与革兰氏阴性人类病原体，即脑膜炎奈瑟氏球菌、脑膜炎奈瑟氏球菌和脑膜炎奈瑟氏球菌的LOS具有相似性。淋病和流感嗜血杆菌。更重要的是，这些常见的碳水化合物表位参与毒力，即粘附、生物膜形成和血清抗性。到目前为止，几乎没有努力来评估M的作用。卡他病LOS。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M.卡他菌LOS的突变体，并且没有确定的突变体可用于描述不同寡糖结构的重要性。我们在这一领域取得了重大进展，在前一时期确定了17个LOS基因，并构建了每个特定的突变体。此外，我们与合作者一起提出了一种潜在的动物定殖模型，这可能是用M进行体内研究的关键。粘膜炎。我们现在可以继续进行遗传学和生物学研究，以验证我们的假设，即由M.卡他分离株与发病机制直接相关。我们进一步假设血清型A和血清型B LOS结构可能提供优于血清型C LOS结构的优势。我们将通过以下具体目标来验证我们的假设：（1）确定M.（2）确定M.卡他病LOS结构的发病机制。 中耳炎在你们这些孩子中很普遍。据估计，超过80%的5岁以下儿童将经历至少一种此类感染。卡他莫拉菌是一种微生物，导致15-20%的所有细菌性中耳感染。这产生了重大的卫生保健问题，并且对确定疫苗靶点有重大兴趣。因此，研究可能作为疫苗抗原的细菌组分（如脂寡糖）至关重要，这是本工作的重点。

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.