Genetics & Biology of M. catarrhalis LOS in Otitis Media

卡他莫拉氏菌是一种革兰氏阴性的人类粘膜病原体，是引起粘膜炎的重要原因。 婴儿和儿童的中耳感染和鼻窦炎， 成人肺部疾病加重。它是中耳炎（OM）的第三大原因， M.卡他，因为50%的儿童将在 生命的前六个月OM的发病率也很高，约80%的儿童在 3岁以下的孩子至少会经历一次。此外，复发性急性OM是普遍的 导致听力受损和发育/学习问题， 学龄。OM是直接和间接卫生保健费用的重要来源，M。catarrhalis 每年有300万到400万的医生就诊。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 旨在确定致病因素的研究。其中一个突出 与毒力因子有关的表面组分是脂寡糖（LOS）。结构 分析证实M.卡他菌LOS与革兰氏阴性菌LOS相似， 人病原体，即脑膜炎奈瑟氏菌（Neisseria meningitidis）、N.淋病和流感嗜血杆菌。 更重要的是，这些共同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。迄今为止， 评价M.卡他病LOS。最有可能的原因是缺乏 这一领域的研究涉及到这样一个事实，即没有数据描述参与的基因， M.卡他病LOS，没有确定的突变体， 可以用来描述不同寡糖结构的重要性。我们有 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， 构建每个特定突变体。此外，我们还提出了一个潜在的动物殖民地 模型，以及我们的合作者，这可能是至关重要的，在进行体内研究， M.粘膜炎。我们现在能够继续进行基因和生物学研究， 验证我们的假设，即M.卡他分离物是 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结构可提供优于血清型C LOS结构的优势。我们将测试我们的 （1）确定涉及的顺序步骤， 组装和生物合成。（2）确定M. catarrhalis 发病机制中的LOS结构。

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.