Molecular Basis for Ocular Surface Tropism in Conjunctivitis

描述（由申请人提供）：本研究的目的是建立一个科学的基础，成本效益的预防结膜炎。细菌性结膜炎是儿童的一种昂贵疾病。美国每年有超过400万的办公室访问量。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， 每年花费超过5亿美元。细菌性结膜炎是由不常见的未被包囊的沙门氏菌引起的。肺炎，其在很大程度上不能在其他身体部位引起疾病，并且是眼睛的唯一致病性。介于眼科和传染病专业之间，这些不寻常的微生物在很大程度上未被研究。一次特别大的、有据可查的结膜炎爆发，涉及达特茅斯学院的698名学生，六个月后，同样的菌株在缅因州的101名幼儿和120名家庭接触者中引起了另一次爆发。疫苗针对的是沙门氏菌的主要毒力因子。肺炎-胶囊。然而，该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独特疾病，在覆盖率方面留下了未解决的差距。如果我们理解了未包囊肺炎球菌对眼表的不寻常嗜性的基础-也就是说，允许它结合和定植在眼睛中的关键因素-我们可以在已经使用的疫苗中包括这些因素的表位，从而预防儿童常见疾病，并节省数亿美元的医疗保健费用，并限制用抗生素治疗儿童的主要原因，现在认为这改变了他们的flra并导致了抗生素耐药性。在初步研究中，我们进行了广泛的比较基因组学研究，以确定候选因素，使未封装的S。肺炎球菌结合到眼表面。这项研究建议通过直接测试最强烈牵连的粘附素和其他定植的优先列表来跟进这些线索 因子，因为它们能够介导与眼表的附着。拟议的研究结合了联合收割机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。

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.