Bacterial biofilms in otitis media

描述（由申请方提供）：本项目旨在确定流感嗜血杆菌脂寡糖组成的变化如何影响生物膜。H.流感生物膜引起慢性中耳炎感染，这是世界上最常见和代价最高的公共卫生问题。中耳炎期间在中耳中形成的生物膜抵抗药物或免疫清除。我们最近发现H.流感病毒生物膜含有唾液酸和磷酸胆碱，其在灰鼠中耳感染模型系统中促进耳炎的进展。 我们假设，在H。流感病毒脂寡糖促进成熟生物膜的形成，从而增加对清除的抗性，并降低先天性应答。为了解决这个假设，我们将完成以下具体目标： 具体目标1：描述脂寡糖组合物如何促进H。流感病毒生物膜表型的体外研究。用于定义成熟生物膜的基准包括降低的宿主炎症反应，以及增加的生物膜密度和结构，其促进对抗生素杀死的抗性。 具体目标2：确定生物膜相关的脂寡糖变化在H。流行性感冒中耳炎我们将使用灰鼠中耳炎动物模型来评估在体外生物膜中观察到的脂寡糖组成的变化如何增加H。流感病毒在体内的持久性和毒力。 这些特定目标的完成将阐明中耳炎和其他慢性感染的关键生物膜生长机制。目前使用的疫苗都不能抵抗未包封的H。引起耳炎的流感病毒株和抗生素耐药性日益限制了这些感染的治疗选择。生物膜对大多数抗生素的固有抗性使这个问题变得更糟。更好地了解生物膜对于合理设计诊断、治疗或预防慢性中耳炎的新方法至关重要。因此，这里提出的研究提供了一个重要的机会，以确定新的目标，以消除全球公共卫生中最昂贵和最普遍的问题之一。

DESCRIPTION (provided by the applicant): This project aims to define how changes in the composition of Haemophilus influenzae lipooligosaccharides affect biofilms. H. influenzae biofilms cause chronic otitis media infections that are among the most common and costly public health problems in the world. Biofilms formed in the middle ear during otitis media resist pharmaceutical or immune clearance. We recently discovered that the lipooligosaccharide glycolipids in H. influenzae biofilms contain sialic acid and phosphorylcholine that contribute to the progression of otitis in a chinchilla middle-ear infection model system. We hypothesize that changes in the composition of H. influenzae lipooligosaccharides promote the formation of mature biofilms, thus increasing resistance to clearance, and decreasing innate responses. To address this hypothesis, we will complete the following Specific Aims: Specific Aim 1: To delineate how lipooligosaccharide composition promotes H. influenzae biofilm phenotypes in vitro. Benchmarks for defining mature biofilms include decreased host inflammatory responses, and increased biofilm density and structure that promotes resistance to killing by antibiotics. Specific Aim 2: To establish the role of biofilm-related changes in lipooligosaccharides in H. influenzae otitis media. We will use the chinchilla animal model for otitis media to evaluate how changes in lipooligosaccharide composition observed in biofilms in vitro increase H. influenzae persistence and virulence in vivo. The completion of these Specific Aims will elucidate biofilm growth mechanisms that are critical to otitis media and other chronic infections. No vaccine in current use protects against the unencapsulated H. influenzae strains that cause otitis, and antibiotic resistance increasingly limits treatment options for these infections. This problem is made even worse by the inherent resistance of biofilms to most antibiotics. A better understanding of biofilms will be crucial to the rational design of new ways to diagnose, treat or prevent chronic otitis media. The research proposed here thus presents an important opportunity to identify new targets for eliminating one of the most costly and prevalent problems in public health worldwide.