Genetics & Biology of M. catarrhalis LOS in Otitis Media

遗传学

• 批准号: 7853873
• 负责人: Anthony A Campagnari
• 金额: $ 17.4万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853873
• 关键词: Acute; Adherence; Adult; Age; Anabolism; Animals; Antibodies; Antibody Formation; Area; Bacteria; Biological Assay; Biology; Carbohydrates; Child; Chinchilla (genus); Clinical; Complement; Coupled; Data; Development; Diagnosis; Disease; Engineering; Epithelial Cells; Epitopes; Genes; Genetic; Glucose; Haemophilus influenzae; Health Care Costs; Healthcare; Human; Incidence; Infant; Infection; Learning; Life; Lower respiratory tract structure; Lung; Lung diseases; Mediating; Membrane; Microbial Biofilms; Modeling; Moraxella (Branhamella) catarrhalis; Mus; Mutate; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Office Visits; Oligosaccharides; Organism; Otitis Media; Pathogenesis; Positioning Attribute; Process; Recurrence; Reporting; Research; Research Design; Resistance; Respiratory Tract Diseases; Role; School-Age Population; Serotyping; Serum; Sinusitis; Site-Directed Mutagenesis; Source; Structure; Surface; Testing; Tympanostomy; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Work; bactericide; beta-Lactamase; ear infection; experience; hearing impairment; in vivo; interest; lipooligosaccharide; middle ear; mutant; pathogen

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.

描述（由申请人提供）：卡他莫拉菌是一种革兰氏阴性的人粘膜病原体，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，卡他性分枝杆菌的定植率很高，50%的儿童在出生后的前6个月就会定植。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，复发性急性OM很普遍，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，每年有300万至400万名卡塔林分枝杆菌到医生办公室就诊。由于鼓室穿刺术不常见，诊断困难，因此认为这种情况较低。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。其中一个与毒力因子有关的重要表面成分是低脂糖（LOS）。结构分析证实，卡他氏分枝杆菌的LOS与革兰氏阴性人类病原体，即脑膜炎奈瑟菌、淋病奈瑟菌和流感嗜血杆菌的LOS有相似之处。更重要的是，这些常见的碳水化合物表位参与了毒力，即粘附，生物膜形成和血清抗性。迄今为止，很少有人努力评价卡他氏分枝杆菌在疾病中的作用。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. catarrhalis LOS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低聚糖结构的重要性。在过去的一段时间里，我们在这一领域取得了重大进展，确定了17个LOS基因并构建了每个特定的突变体。此外，我们已经提出了一个潜在的动物定植模型，与我们的合作者一起，这可能是关键的进行体内研究M. catarrhalis。我们现在能够继续进行遗传和生物学研究，以验证我们的假设，即卡他氏分枝杆菌分离株组装的血清型LOS结构与发病机制直接相关。我们进一步假设，血清A型和血清B型LOS结构可能比血清C型LOS结构具有优势。我们将通过以下具体目标来验证我们的假设：(1)确定M. catarrhalis LOS的组装和生物合成的顺序步骤；(2)确定M. catarrhalis LOS结构在发病机制中的作用。