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

• 批准号: 8163415
• 负责人: Lauren O Bakaletz
• 金额: $ 49.53万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 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/8163415
• 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' 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

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. PUBLIC HEALTH RELEVANCE: There were 24.5 million physician's office visits made for middle ear infections [or otitis media (OM)] in 1990 in the United States alone. Moreover, worldwide it is reported that between 65 and 330 million children suffer from chronic secretory OM, 60% of which have an associated hearing loss from this disease state that is characterized by chronically draining ears that can extend over a period of years. The most cost-effective way to manage this highly prevalent pediatric disease, and have a transformational effect on the health of children globally, is through the development of novel methods to better treat OM, as well as the design of innovative vaccines to prevent OM, both of which are the overarching goals of our collaborative research program.

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的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，为了设计新的和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，包括其独特的生物化学和蛋白质组组成，以及如何破坏这些结构来介导治疗性或预防性“治愈”。为此，我们提出了一系列三个高度综合的具体目标。通过这些目标中提出的实验的成功进行，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内存在的细胞外DNA（eDNA）的细菌蛋白对于在体外和体内减少或根除该结构非常有效。此外，我们将开始确定这种有效策略的分子机制，试图解开所观察到的保护的免疫相关性，扩大研究，探索针对IHF的抗体之间观察到的协同作用（DNA结合蛋白）和其它酶、抗体和/或抗生素，然后将我们先进的理解应用于设计和测试新的候选疫苗和治疗方法，用于使用这种重要的多微生物疾病的灰鼠模型预防或治疗OM，分别OM的龙猫模型代表了这种高度流行的儿科疾病的一种稳健的、可重复的和广泛研究的动物模型，在该模型中建立了这些基本的原理证明发现。此外，尽管我们的疾病干预的主要目标是OM，但由于NTHI导致许多人类呼吸道生物膜相关疾病，因此本文提出的研究也可能为气道其他部位（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（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》（第28章：视力和听力，第28-12节）和《2009-2011财政年度NIDCD战略计划》，其中一个优先研究领域是正常和紊乱交流过程的分子和非遗传基础。具体而言，我们将继续我们的长期努力，“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OM导致的听力损失），这是战略计划优先领域I的目标。 公共卫生相关性：仅在美国，1990年就有2450万人因中耳感染[或中耳炎（OM）]而就诊。此外，据报道，全世界有6500万至3.3亿儿童患有慢性分泌性OM，其中60%的儿童患有与这种疾病状态相关的听力损失，其特征在于可以持续数年的长期耳朵排水。管理这种高度流行的儿科疾病并对全球儿童健康产生变革性影响的最具成本效益的方法是通过开发新方法来更好地治疗OM，以及设计创新疫苗来预防OM，这两者都是我们合作研究计划的首要目标。