Molecular Basis for Ocular Surface Tropism in Conjunctivitis

结膜炎眼表向性的分子基础

• 批准号: 8670576
• 负责人: Michael S Gilmore
• 金额: $ 41万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670576
• 关键词: Accounting; Agglutinins; Antibiotic Resistance; Antibiotics; Antigens; Bacteria; Bacterial Adhesins; Bacterial Capsules; Bacterial conjunctivitis; Base Sequence; Binding; Binding Proteins; Biological; Campylobacter; Child; Childhood; Choline; Communicable Diseases; Conjunctivitis; Development; Disease; Disease Outbreaks; Enzymes; Epidemic; Epithelial Cells; Epitopes; Event; Eye; Eye Infections; Family; Genes; Genetic; Genetic Polymorphism; Genome; Genomics; Goals; Health Care Costs; Healthcare Systems; Homologous Gene; Infection; Infection prevention; Lead; Left; Lipoproteins; Maine; Measures; Mediating; Microbe; Molecular; Movement; Neuraminidase; Office Visits; Ophthalmology; Pathogenicity; Pathogenicity Island; Prevention; Preventive; Property; Proteins; Research; Respiratory Tract Infections; Site; Streptococcus; Streptococcus pneumoniae; Students; Surface; Testing; Therapeutic; Tropism; Vaccines; Virulence Factors; Work; base; capsule; college; comparative; comparative genomics; cost; cost effective; falls; follow-up; genome analysis; insertion/deletion mutation; medical specialties; novel; ocular surface; pressure; prevent; public health relevance; receptor; sound

DESCRIPTION (provided by applicant): The GOAL of this research is to establish a scientific basis for cost effective prevention of conjunctivitis. Bacterial conjunctivitis is a costly diseaseof children. There are > 4 million office visits in the US/yr. Among the most common infections of childhood, it is a leading cause for antibiotic use. Half of cases occur in children under 9 years, with an annual cost of over $500 million. Bacterial conjunctivitis is caused by unusual strains of unencapsulated S. pneumoniae that are largely incapable of causing disease at other body sites and are uniquely pathogenic for the eye. Falling between specialties of Ophthalmology and Infectious Diseases, these unusual microbes have largely gone unstudied. An especially large and well documented conjunctivitis outbreak, involving 698 students at Dartmouth College, and six months later, the same strain caused another outbreak among 101 young children and 120 family contacts in Maine. Vaccines target the primary virulence factor of S. pneumoniae - the capsule. However, the vaccine is completely ineffective in preventing conjunctivitis, a disease uniquely caused by strains that lack the capsule, leaving an unaddressed gap in coverage. If we understood the basis for the unusual tropism of unencapsulated pneumococci for the ocular surface - that is, the key factors allowing it to bind and colonize the eye - we could include epitopes of these factors in the vaccine already being used, thereby preventing a common disease of childhood, and saving hundreds of $ million in health care costs, and limiting a leading cause for treating children with antibiotics, which is now believed to be altering their flra as well as leading to antibiotic resistance. In preliminary studies, we undertook an expansive comparative genomics study to identify candidate factors that allow unencapsulated S. pneumoniae to bind to the ocular surface. This research proposes to follow up these leads by directly testing a prioritized list of the most strongly implicated adhesins and other colonization factors, for their ability to mediate attachment to the ocular surface. The proposed studies combine biological approaches, as well as state-of-the-art genomics approaches, to identify the most important colonization factors that lead to conjunctivitis.

描述（由申请人提供）：本研究的目标是为成本有效的预防结膜炎建立科学基础。细菌性结膜炎是一种代价高昂的儿童疾病。美国每年有超过 400 万人次到访办公室。在儿童最常见的感染中，它是使用抗生素的主要原因。一半的病例发生在9岁以下的儿童中， 每年的成本超过5亿美元。细菌性结膜炎是由不寻常的无包膜肺炎链球菌菌株引起的，这些菌株基本上不能在身体其他部位引起疾病，并且对眼睛具有独特的致病性。这些不寻常的微生物介于眼科和传染病专业之间，基本上没有得到研究。达特茅斯学院 (Dartmouth College) 发生了一次规模特别大且有据可查的结膜炎爆发，涉及 698 名学生，六个月后，同一菌株在缅因州 101 名幼儿和 120 名家庭接触者中再次爆发。疫苗针对的是肺炎链球菌的主要毒力因子——荚膜。然而，该疫苗在预防结膜炎方面完全无效，结膜炎是一种仅由缺乏荚膜的菌株引起的疾病，在覆盖范围上留下了未解决的空白。如果我们了解非包膜肺炎球菌对眼表的不寻常趋向性的基础，即允许其结合并定植眼睛的关键因素，我们就可以将这些因子的表位包含在已使用的疫苗中，从而防止常见的肺炎球菌感染。儿童疾病，节省数亿美元的医疗费用，并限制使用抗生素治疗儿童的主要原因，目前认为抗生素正在改变他们的菌群并导致抗生素耐药性。在初步研究中，我们进行了一项广泛的比较基因组学研究，以确定允许未包膜肺炎链球菌与眼表结合的候选因素。这项研究建议通过直接测试最强烈相关的粘附素和其他定植的优先列表来跟踪这些线索 因素，因为它们能够介导与眼表的附着。拟议的研究结合了生物学方法以及最先进的基因组学方法，以确定导致结膜炎的最重要的定植因素。