Novel immunotherapeutics for the management of otitis media due to H. influenzae

描述(由申请人提供)：最近在我们对非分型流感嗜血杆菌(NTHI)引起的中耳炎(OM)的发病机制的理解上有了巨大的进步。值得注意的是，我们已经认识到生物膜在NTHI诱导的OM的慢性化和复发中所起的作用。细菌栖息在生物膜内，对免疫和抗生素治疗的效应者构成了巨大的障碍。因此，为了设计新的有效策略来更好地治疗和/或预防OM，有必要了解生物膜的生物学，包括它们独特的生物化学和蛋白质组组成，以及人们如何破坏这些结构来调节治疗性或预防性的“治愈”。为此，我们在这里提出了一系列高度整合的具体目标。通过这些目标中提议的实验的成功进行，我们将扩展非常有希望的初步数据，这些数据表明，靶向稳定生物膜结构中存在的细胞外DNA(EDNA)的细菌蛋白在体外和体内都可以高效地减少或根除这种结构。此外，我们将开始定义这一有效策略背后的分子机制，试图揭开观察到的保护的免疫相关性，扩大研究，探索针对IHF(一种DNA结合蛋白)的抗体与其他酶、抗体和/或抗生素之间的观察到的协同作用，然后将我们的先进知识应用于使用这种重要的多微生物疾病的栗鼠模型分别预防或治疗OM的新型候选疫苗和疗法的设计和测试。龙猫OM模型代表了这种高度流行的儿科疾病的健壮、可重复性和广泛研究的动物模型，在该模型中建立了这些基本的原则证明发现。此外，虽然我们疾病干预的主要目标是OM，因为NTHI导致了许多与生物膜相关的人类呼吸道疾病，这里提出的研究也可能为治疗呼吸道其他部位的疾病提供更好的方法，如鼻窦(慢性鼻-鼻窦炎)、扁桃体和腺样体(扁桃体炎、腺体炎)、支气管(慢性咳嗽和支气管炎)和肺(COPD、早期CF、社区获得性肺炎)。因此，我们的目标完全符合2010年健康人(28：视觉和听力，第28-12节)和NIDCD 2009-2011年战略计划，其中优先研究领域是正常和无序沟通过程的分子和非遗传基础。具体地说，我们将继续我们长期的努力，“探索导致沟通障碍的病毒和细菌感染的发病机制、治疗和预防”(即，由于OM造成的听力损失)，这是战略计划优先领域I的目标。

DESCRIPTION (provided by applicant): There have been tremendous recent advances in our understanding of the pathogenesis of otitis media (OM) due to nontypeable Haemophilus influenzae (NTHI). Significantly, we've come to appreciate the role that biofilms play in the chronicity and recurrence of NTHI-induced OM. Bacteria dwelling within a biofilm present a formidable obstacle to effectors of immunity and antibiotic therapies. Thereby, in order to design novel and effective strategies to better treat and/or prevent OM, it is necessary to understand both the biology of biofilms, including their unique biochemical and proteomic composition, as well as how one might undermine these structures to mediate a therapeutic or preventative 'cure'. To do so, herein we propose a series of three highly integrated specific aims. Through the successful conduct of the experimentation proposed in these aims, we will expand upon highly promising preliminary data which show that targeting a bacterial protein that stabilizes extracellular DNA (eDNA) present within a biofilm structure is highly effective for reducing or eradicating that structure both in vitro and in vivo. Moreover, we will begin to define the molecular mechanisms that underlie this effective strategy, attempt to unravel the immune correlates of the observed protection, expand upon studies that will explore the observed synergy between antibodies directed against IHF (a DNA binding protein) and other enzymes, antibodies and/or antibiotics, then apply our advanced understanding to the design and testing of novel vaccine candidates and therapeutics for the prevention or treatment of OM using a chinchilla model of this important polymicrobial disease, respectively. The chinchilla model of OM represents a robust, reproducible and extensively studied animal model of this highly prevalent pediatric disease in which to establish these essential proof-of-principle findings. Moreover, whereas our primary target for disease intervention is OM, because NTHI causes many biofilm-associated diseases of the human respiratory tract, the studies proposed here will also likely provide better approaches to use for disease in other parts of the airway such as the sinuses (chronic rhinosinusitis), the tonsils and adenoids (tonsillitis, adenoiditis), the bronchus (chronic cough and bronchitis) and the lung (COPD, early stage CF, community acquired pneumonia). Our goals are thus fully in keeping with both Healthy People 2010 (28: Vision and Hearing, Section 28-12), and the NIDCD strategic plan FY 2009-2011, wherein a priority research area is Molecular and Non-genetic Basis of Normal and Disordered Communication Processes. Specifically, we will continue our long-standing efforts to "explore the pathogenesis, treatment and prevention of viral and bacterial infections that contribute to communication disorders" (i.e. hearing loss due to OM), a goal of Strategic Plan Priority Area I.