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）：卡他莫拉氏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，也是成人肺部疾病恶化的重要来源。它是中耳炎 (OM) 的第三大原因，并且粘膜炎莫拉氏菌的定植率很高，因为 50% 的儿童会在生命的前 6 个月内定植。 OM 的发病率也很高，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 是直接和间接医疗费用的重要来源，卡他莫拉菌每年导致 3 至 400 万人次就诊。由于鼓室穿刺术不常见，因此诊断很困难，因此该值被认为较低。这些事实刺激了旨在确定参与发病机制的毒力因子的研究。作为毒力因子的重要表面成分之一是脂寡糖（LOS）。结构分析证实，卡他莫拉菌 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 具有相似性。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、生物膜形成和血清抗性。迄今为止，很少有人努力评估卡他莫拉氏菌 LOS 在疾病中的作用。该领域缺乏研究的最可能原因是没有数据描述卡他莫拉菌 LOS 生物合成和组装所涉及的基因，也没有明确的突变体可用于描述不同寡糖结构的重要性。前期我们在这一领域取得了重大进展，鉴定了 17 个 LOS 基因并构建了每个特定突变体。此外，我们与我们的合作者一起提出了一种潜在的动物定植模型，这对于进行卡他莫拉氏菌的体内研究可能至关重要。我们现在可以继续进行遗传和生物学研究，旨在检验我们的假设，即卡他莫拉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。我们将通过以下具体目标来检验我们的假设：（1）确定卡他莫拉氏菌 LOS 组装和生物合成所涉及的顺序步骤；（2）确定卡他莫拉氏菌 LOS 结构在发病机制中的作用。 中耳感染在你们的孩子中相当普遍。据估计，超过 80% 的 5 岁以下儿童至少会经历其中一种感染。卡他莫拉氏菌是一种导致 15-20% 细菌性中耳感染的微生物。这产生了重大的医疗保健问题，并且人们对确定疫苗靶标非常感兴趣。因此，研究可能成为疫苗抗原的细菌成分（例如脂寡糖）至关重要，这是这项工作的重点。