Effect of the Middle Ear Inflammation on the Inner Ear

描述（由申请人提供）：中耳炎（OM）是最常见的儿童疾病之一，也是一个主要的公共卫生问题。该病可导致中耳和内耳病变和听力丧失。我们对OM中的细菌病原体如何引起中耳炎症反应、中耳和内耳相互作用的机制、内耳病理和听力损失的理解存在根本性的空白。这促使我们对感染因子从中耳向内耳迁移的分子过程以及这种迁移对耳部病理的影响进行了有说服力的研究。抗生素的广泛使用导致耐抗生素肺炎链球菌的增加，慢性OM发展及其并发症的可能性增加。虽然多糖疫苗已经开发出来，但肺炎链球菌有90多种不同的血清型，针对一种血清型的抗体通常不能预防另一种血清型。目前的7价肺炎球菌结合疫苗PCV7对2岁以下儿童侵袭性肺炎球菌病的有效性为100%，但对急性OM的有效性仅为34%。基于蛋白质的疫苗可以通过包含在不同肺炎球菌血清型中保守的抗原来克服这一限制。我们的长期目标是开发预防和治疗OM及其并发症的新方法。在此应用中，我们提出了一种新的策略来预防OM及其并发症，该策略依赖于PspA和其他肺炎球菌蛋白的组合。我们将利用不同的突变菌株和动物免疫来对抗这些蛋白质。我们的目标是了解细菌毒力因子在中耳和内耳细菌入侵、定植和发病机制中的作用，以进行治疗靶向，并开发一种疫苗组合物，以最佳地中和最关键的蛋白质毒力因子。我们的中心假设是PspA和其他细菌蛋白影响中耳和内耳的病理。中耳产生的细菌成分和炎症介质通过圆窗膜进入内耳，破坏耳蜗结构，导致听力丧失。我们的基本原理是，了解细菌成分如何影响中耳和内耳的病理，将使设计预防和治疗OM的新方法成为可能。这些考虑导致了我们的具体目标的制定：1)确定肺炎球菌PspA蛋白及其与其他潜在肺炎球菌疫苗蛋白在中耳和内耳的作用和预防OM的策略；2)探讨活体肺炎链球菌引起内耳损伤和听觉功能障碍的机制。从这些研究中获得的结果将为肺炎链球菌毒力因子在OM和内耳并发症发展中的作用提供新的见解。为了实现我们的目标，我们召集了一群近年来合作过的pi，他们具有独特的资格，可以利用他们的综合专业知识应对这一挑战。

DESCRIPTION (provided by applicant): Otitis media (OM) is one of the most common of childhood diseases and a major public health problem. The disease can lead to middle ear and inner ear pathology and hearing loss. There are fundamental gaps in our understanding of how bacterial pathogens in OM cause the inflammatory response in the middle ear, the mechanism of middle and inner ear interaction, inner ear pathology, and hearing loss. This prompted us to develop a cogent investigation of the molecular processes underlying migration of infectious agents from the middle to the inner ear and the effects of such migration on the ear pathology. Widespread use of antibiotics has resulted in an increase of antibiotic-resistant Streptococcus pneumoniae and an increased potential for chronic OM development and its complications. Although polysaccharide vaccines have been developed, there are more than 90 distinct serotypes for S. pneumoniae, and antibodies against one serotype generally do not protect against another. The current 7-valent pneumococcal conjugate vaccine PCV7 is 100% efficacious against invasive pneumococcal disease of vaccine serotypes in children < 2-years old, but only 34% against acute OM. A protein-based vaccine may overcome this limitation by including antigens conserved among different pneumococcal serotypes. Our long-term goal is to develop novel approaches for prevention and treatment of OM and its complications. In this application, we propose a new strategy for prevention of OM and its complications that relies on a combination of PspA and other pneumococcal proteins. We will utilize different mutant bacterial strains and immunization of animals against these proteins. Our objective is to understand the role of bacterial virulence factors in bacterial invasion, colonization, and pathogenesis in the middle and inner ears for therapeutic targeting and to develop a vaccine composition that optimally neutralizes the most critical protein virulence factors. Our central hypothesis is that PspA and other bacterial proteins affect the pathology of the middle and inner ears. Bacterial components and inflammatory mediators produced in the middle ear pass through the round window membrane into the inner ear, damage cochlear structures, resulting in hearing loss. Our rationale is that knowing how bacterial components affect the pathology of the middle and inner ears will make it possible to design new approaches for the prevention and treatment of OM. These considerations have led to the formulation of our Specific Aims: 1) To identify the role of pneumococcal PspA protein and its combination with other potential pneumococcal vaccine proteins on the middle and inner ear and strategies for prevention of OM; 2) To identify mechanisms of inner ear damage and auditory dysfunction caused by live S. pneumoniae. The results gained from these studies will provide new insights into the roles of S. pneumoniae virulence factors in the development of OM and inner ear complications. To achieve our goal we have assembled a group of PIs who have collaborated in recent years, and who are uniquely qualified to address this challenge with their combined expertise. PUBLIC HEALTH RELEVANCE: These studies will use innovative approaches to determine the effects of important pneumococcal virulence proteins and their combination on the middle and inner ears. Understanding the role of bacterial virulence factors and host defense using mutant strains and immunization experiments may have an important positive impact to facilitate the development of new strategies for prevention and treatment of otitis media and its complications, especially significant in the era of multi-drug resistant bacteria, by selection of bacterial proteins for future vaccine design against pneumococcal otitis media, such as protein- based or conjugate polysaccharide vaccine with pneumococcal proteins as carriers.