Bacterial biofilms in otitis media

描述(由申请人提供)：此申请是R01项目的竞争性续签，该项目的重点是确定中耳炎感染期间生物膜中细菌持久性的决定因素。中耳炎是由呼吸道机会主义者引起的，如流感嗜血杆菌(Hi)，它形成的生物膜群落促进细菌在中耳室内的持久性。在支持的最初四年中，我们确定了Hi参与生物膜形成的机制(S)，并证明了生物膜促进细菌在体内的持久性。在下一个项目期间，我们将确定生物膜抵抗宿主清除的决定因素。我们假设，生物膜促进了细菌对清除的抵抗力，因为生物膜内的细菌应激反应被激活，以及对宿主吞噬细胞的固有抵抗力。为了解决这些假说，我们将完成以下具体目标：具体目标1：描述细菌应激反应在实验性中耳炎高持续性中的作用(S)。特定目的2：确定Hi生物膜对吞噬细胞和细胞外杀伤的抵抗力。虽然很明显，生物膜的生长模式与大多数持续性感染有关，但关于细菌对生物膜内清除的抵抗力的决定因素，仍有许多需要了解。拟议工作的完成将增强我们对生物膜在中耳炎临床背景下的作用的理解。 与公共卫生相关：中耳炎是一种世界范围内常见且代价高昂的主要儿科疾病，每年造成的总经济影响高达数十亿美元。中耳炎感染是儿科就诊的主要原因，新的抗生素处方，以及外科注射鼓室引流管以缓解慢性和复发性中耳炎是美国最常见的外科手术。长期以来，流感嗜血杆菌一直被认为是导致中耳炎的最常见细菌原因，现在很明显，流感嗜血杆菌形成生物膜是持续感染的重要决定因素。这一应用的重点是了解这些生物膜群落如何促进细菌在体内的持久性。了解细菌是如何形成这些生物膜的，将是学习更好地诊断、预防和/或治疗慢性感染的重要一步。

DESCRIPTION (provided by applicant): This application is for competitive renewal of an R01 project focused on defining determinants of bacterial persistence in biofilms during otitis media infections. Otitis media is caused by airway opportunists such as Haemophilus influenzae (Hi, which forms biofilm communities that promote bacterial persistence within the middle-ear chamber. During the first four years of support we have defined mechanism(s) involved in biofilm formation by Hi, and proved that biofilms promote bacterial persistence in vivo. For the next project period we will define determinants of biofilm resistance to host clearance. We hypothesize that biofilms promote bacterial resistance to clearance because of activation of bacterial stress-responses within the biofilm, and inherent resistance to host phagocytes. In order to address these hypotheses we will complete the following Specific Aims: Specific Aim 1: To delineate role(s) of bacterial stress-responses in Hi persistence during experimental otitis media. Specific Aim 2: To define resistance of Hi biofilms to phagocytic and extracellular killing. Although it is clear that the biofilm mode of growth is involved in the majority of persistent infections, much remains to be learned about the determinants of bacterial resistance to clearance within biofilms. The completion of the proposed work will enhance our understanding of the role of biofilms within the clinical context of otitis media. PUBLIC HEALTH RELEVANCE: Otitis media is a major common and costly pediatric illness worldwide, accounting for billions of dollars per year in total economic impact. Otitis media infections are the leading reason for pediatric office visits, new antibiotic prescriptions, and surgical instillation of tympanic drain tubes to relieve chronic and recurrent otitis media is the most commonly performed surgical procedure in the U.S. Haemophilus influenzae has long been recognized as the most common bacterial causes of otitis media, and it is now clear that H. influenzae forms biofilms that are important determinants of persistent infections. The focus of this application is to understand how these biofilm communities promote bacterial persistence in vivo. Understanding how bacteria form these biofilms will be an important step in learning to better diagnose, prevent, and/or treat chronic infections.