Bacterial biofilms in otitis media

描述(由申请人提供)：该项目旨在确定流感嗜血杆菌脂低聚糖组成的变化如何影响生物膜。流感嗜血杆菌生物被膜导致慢性中耳炎感染，这是世界上最常见和代价高昂的公共卫生问题之一。中耳炎期间在中耳形成的生物膜抵抗药物或免疫清除。我们最近发现，流感嗜血杆菌生物膜中的脂寡糖糖脂含有唾液酸和磷胆碱，在栗鼠中耳感染模型系统中，这两种物质有助于中耳炎的进展。 我们推测，流感嗜血杆菌脂低聚糖组成的变化促进了成熟生物膜的形成，从而增加了对清除的抵抗力，降低了固有反应。为了解决这一假设，我们将完成以下具体目标： 具体目的1：体外研究脂寡糖组成对流感嗜血杆菌生物膜表型的促进作用。定义成熟生物膜的基准包括减少宿主炎症反应，以及增加生物膜密度和结构，以提高对抗生素杀戮的抵抗力。 具体目的2：确定与生物膜相关的脂寡糖变化在流感嗜血杆菌中耳炎中的作用。我们将使用栗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体内流感嗜血杆菌的持久性和毒力。 这些特定目标的完成将阐明对中耳炎和其他慢性感染至关重要的生物膜生长机制。目前使用的疫苗都不能预防引起中耳炎的未包裹的流感嗜血杆菌菌株，而抗生素耐药性越来越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耐药性使这个问题变得更加严重。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，这里提出的研究为确定新的目标，消除世界范围内最昂贵和最普遍的公共卫生问题之一提供了一个重要机会。

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.