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

用于治疗流感嗜血杆菌引起的中耳炎的新型免疫疗法

基本信息

批准号：
8303220
负责人：
Lauren O Bakaletz
金额：
$ 56.32万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303220
关键词：
Accident and Emergency department Acute Adaptive Behaviors Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Antibodies Area Bacteria Bacterial Infections Bacterial Proteins Behavior Benign Biochemical Biology Bronchi Bronchitis Child Child health care Childhood Chinchilla (genus)Chronic Chronic Obstructive Airway Disease Communication impairment Communities Coughing DNA DNA-Binding Proteins Data Development Disease Ear Ensure Enzymes Fostering Foundations General Anesthesia Goals Haemophilus influenzae Healthy People 2010 Hearing Human Immune Immunity Immunization Immunotherapeutic agent In Vitro Intervention Laboratories Licensure Life Lung Mediating Membrane Proteins Methods Microbial Biofilms Modeling Molecular National Institute on Deafness and Other Communication Disorders Natural Immunity Nontypable Haemophilus influenza Office Visits Operative Surgical Procedures Otitis Media Otitis Media with Effusion Pathogenesis Physicians&apos Offices Play Pneumonia Prevention Process Proteomics Recurrence Relative (related person)Reporting Research Research Priority Resolution Respiratory System Respiratory tract structure Role Series Sinus Staging Strategic Planning Streptococcus pneumoniae Structure Tertiary Protein Structure Testing Therapeutic Time Tonsil Tonsillitis United States Vaccines Virus Diseases Vision Visit acquired immunity base chronic rhinosinusitis cost effective design driving force ear infection experience extracellular hearing impairment human disease improved in vivo innovation killings member microorganism middle ear non-genetic novel novel vaccines pathogen prevent programs protective efficacy residence resistant strain sobriety vaccine candidate vaccine development

项目摘要

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.

描述（由申请人提供）：我们对不可分型流感嗜血杆菌（NTHI）引起的中耳炎（OM）发病机制的理解最近取得了巨大进展。值得注意的是，我们已经认识到生物膜在 NTHI 诱导的 OM 慢性化和复发中所起的作用。生物膜内的细菌对免疫和抗生素治疗的效应器构成了巨大的障碍。因此，为了设计新颖有效的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，包括其独特的生化和蛋白质组组成，以及如何破坏这些结构以介导一种治疗性或预防性“治愈”。为此，我们在此提出了一系列三个高度综合的具体目标。通过成功进行这些目标中提出的实验，我们将扩展非常有希望的初步数据，这些数据表明，针对稳定生物膜结构中存在的细胞外 DNA (eDNA) 的细菌蛋白，对于减少或消除该结构非常有效。体外和体内。此外，我们将开始定义这一有效策略背后的分子机制，尝试阐明所观察到的保护的免疫相关性，扩展研究，探索针对 IHF（一种 DNA 结合蛋白）的抗体与其他酶之间观察到的协同作用、抗体和/或抗生素，然后分别使用这种重要的多微生物疾病的龙猫模型，应用我们先进的理解来设计和测试用于预防或治疗 OM 的新型候选疫苗和疗法。 OM 的龙猫模型代表了这种高度流行的儿科疾病的稳健、可重复且经过广泛研究的动物模型，在该模型中建立了这些重要的原理验证发现。此外，虽然我们疾病干预的主要目标是 OM，但由于 NTHI 会引起许多与人类呼吸道生物膜相关的疾病，因此本文提出的研究也可能为治疗呼吸道其他部位（例如鼻窦）的疾病提供更好的方法（慢性鼻窦炎）、扁桃体和腺样体（扁桃体炎、腺样体炎）、支气管（慢性咳嗽和支气管炎）和肺（慢性阻塞性肺病、早期 CF、社区获得性肺炎）。因此，我们的目标完全符合《健康人 2010》（28：视力和听力，第 28-12 节）和 NIDCD 2009-2011 财年战略计划，其中优先研究领域是正常和听力的分子和非遗传基础。沟通过程混乱。具体来说，我们将继续长期努力“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 OM 引起的听力损失），这是战略计划优先领域 I 的目标。