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）：卡他氏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，也是成年人肺部疾病的重要来源。这是中耳炎（OM）的第三大主要原因，卡塔尔哈利菌（M. cartarrhalis）的定殖率很高，因为50％的儿童将在生命的前6个月内被殖民。 OM的发病率也很高，大约80％的3岁以下儿童将至少经历一集。此外，随着这些孩子达到学龄的年龄，反复的急性OM普遍存在导致听力障碍和发展/学习问题。 OM是直接和间接医疗保健费用的重要来源，Cartarrhalis M. Cartarrhalis每年造成3至400万个医师办公室访问。由于诊断困难，因此认为这很低，因为鼓膜穿刺术并不常见。这些事实刺激了旨在识别发病机理涉及的毒力因素的研究。涉及毒力因子的突出表面成分之一是脂肪糖（LOS）。结构分析证实，Cartarrhalis Los M.与革兰氏阴性人类病原体的LO有相似性，即Neisseria Meningitis，N。Gono​​rrhoeae和Haemophilus hapyzae。更重要的是，这些常见的碳水化合物表位参与毒力，即粘附，生物膜形成和血清耐药性。迄今为止，几乎没有努力评估卡塔哈里斯分枝杆菌在疾病中的作用。在这一领域缺乏研究的最可能原因是，没有数据描述与Cartarrhalis M. cartarrhalis Los的生物合成和组装有关的基因，并且没有可以用来描述不同寡糖结构的重要性的确定突变体。在上一时期，我们在这一领域取得了重大进展，识别17个LOS基因并构建每个特定突变体。此外，我们提出了一个潜在的动物定植模型，以及我们的合作者，这对于与Cartarrhalis进行体内研究至关重要。现在，我们可以继续旨在检验我们的假设，即由Cartarrhalis分离株组装的血清型LOS结构与发病机理直接相关。我们进一步假设血清型A和血清型B LOS结构可能比血清型C LOS结构具有优势。我们将通过以下特定目的检验我们的假设：（1）确定卡塔尔哈利菌M. cartarrhalis los的组装和生物合成所涉及的顺序步骤，（2）确定Cartarrhalis M. cartarrhalis Los结构在发病机理中的作用。 中耳感染在您的孩子中很普遍。据估计，超过80％的5岁儿童将至少经历此类感染中的至少一种。莫拉氏菌Catarrhalis是一种生物体，可引起所有细菌中耳感染的15-20％。这产生了重大的医疗保健问题，并且对识别疫苗靶标感兴趣。因此，研究可能是疫苗抗原的细菌成分，例如这项工作的重点是疫苗的抗原。