Molecular Basis for Ocular Surface Tropism in Conjunctivitis

描述(申请人提供)：本研究的目的是为有效预防结膜炎提供科学依据。细菌性结膜炎是一种代价高昂的儿童疾病。美国每年有400万人次的办公室来访。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， 每年耗资超过5亿美元。细菌性结膜炎是由不寻常的未被包裹的肺炎链球菌引起的，这种肺炎链球菌在很大程度上不能在其他身体部位引起疾病，对眼睛是唯一的致病因素。这些不同寻常的微生物介于眼科学和传染病之间，在很大程度上没有得到研究。达特茅斯学院爆发了一场规模特别大且有充分证据的结膜炎疫情，涉及698名学生，六个月后，同样的菌株在缅因州101名幼儿和120名家庭接触者中再次爆发。疫苗针对肺炎链球菌的主要毒力因素--衣壳。然而，这种疫苗在预防结膜炎方面完全无效，结膜炎是一种由缺乏胶囊的菌株引起的疾病，在覆盖范围内留下了一个未解决的缺口。如果我们了解了无胶囊肺炎球菌对眼睛表面不寻常的趋向性的基础--也就是允许它结合和定植眼睛的关键因素--我们就可以在已经使用的疫苗中包括这些因素的表位，从而预防一种常见的儿童疾病，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，现在据信这会改变他们的Fla，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，以确定允许未包裹的肺炎链球菌与眼表面结合的候选因素。这项研究建议通过直接测试最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，因为它们有能力调解附着到眼睛表面。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居因素。

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.