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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：
9757755
负责人：
Lauren O Bakaletz
金额：
$ 59.1万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757755
关键词：
Acute Adenoidal structure Adolescent Adult Affect Anatomy Animal Model Antibiotic Therapy Antibiotics Antibodies Applications Grants Architecture Area Bacteria Bacterial DNA Bacterial Infections Biochemical Biological Biology Bronchi Bronchitis Characteristics Child Child Health Childhood Chinchilla (genus)Chronic Chronic Obstructive Airway Disease Clinical Communication impairment Communities Coughing DNA DNA-Binding Proteins Development Diagnosis Disease Dose Drainage procedure Ear Elements Epitope Mapping Epitopes Etiology Excision Experimental Models Extracellular Matrix Face Family Foundations Goals Grant Haemophilus influenzae Healthy People 2020 Hearing Immune Immunity Immunotherapeutic agent In Vitro Incubated Integration Host Factors Intervention Kinetics Laboratories Lead Life Literature Lung Lung diseases Mediating Methods Microbial Biofilms Monoclonal Antibodies National Institute on Deafness and Other Communication Disorders Nontypable Haemophilus influenza Operative Surgical Procedures Otitis Media Otorrhea Outcome Pathogenesis Perforation Phenotype Play Pneumonia Positioning Attribute Prevention Proteins Proteomics Pus Recurrence Reporting Reproducibility Research Research Priority Resolution Respiratory System Role Running Sensory Disorders Series Side Sinus Solid Strategic Planning Structure Suppurative Otitis Media Therapeutic Tonsil Tonsillitis Treatment Efficacy Treatment Failure Tubal Occlusion Tube Tympanic membrane Tympanostomy Tympanostomy Tube Insertions Vaccines Work World Health Organization chronic rhinosinusitis cost effective design experience extracellular hearing impairment human disease human pathogen improved in vivo innovation mucosal biofilms novel novel therapeutic intervention pathogen preclinical study prevent programs therapeutic target therapy development

项目摘要

PROJECT SUMMARY 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 both post-tympanostomy tube otorrhea as well as 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 otorrhea and 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 ‘cure’. Through the successful conduct of a series of three highly integrated Specific Aims, we will expand upon a solid foundation of a growing body of literature from our laboratories which show that we can target a family of bacterial DNA-binding proteins (IHF and HU) that are critical to stabilize extracellular DNA (eDNA) present within an NTHI biofilm to reduce or eradicate that structure both in vitro and in vivo. Here, we will now identify and characterize the best therapeutic antigenic targets within both IHF and HU, with a focus on specific functional domains. We will also determine both the kinetics of release and the availability of IHF and HU subunits within the NTHI eDNA-DNABII dependent extracellular matrix in order to identify an optimal therapeutic window for intervention. Moreover, we will determine the therapeutic value of using biofilm-focused, epitope-targeted monoclonal antibodies and cocktails thereof to resolve biofilms associated with chronic otorrhea and otitis media. These latter studies will first be conducted in vitro using both monospecies biofilms, as well as those of mixed otopathogen etiology, to better reflect the clinical condition. Finally, we will determine the relative therapeutic efficacy of this approach in vivo, using a chinchilla model of experimental OM. The chinchilla represents an anatomically appropriate, robust, reproducible and extensively studied animal model of this highly prevalent pediatric biofilm disease in which to conduct these essential pre-clinical studies. Importantly, 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 a basis for the design of better practices to treat 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 Specific Aims are perfectly aligned with both Healthy People 2020 (Hearing and Other Sensory or Communication Disorders, ENT-VSL-2: “Reduce otitis media in children and adolescents”), and the NIDCD strategic plan FY 2012-2016, wherein Priority Research Area 3 – Improving Diagnosis, Treatment and Prevention, declares a mandate to “Develop therapies to prevent and treat biofilms.”

项目摘要近年来，人们对中耳炎发病机制的认识有了很大的进展流感嗜血杆菌（NTHI）重要的是，我们已经开始意识到生物膜在鼓膜造孔术后管耳畸形以及NTHI的慢性化和复发中起作用，诱导OM。居住在生物膜内的细菌对免疫效应子和免疫抑制剂构成了巨大的障碍。抗生素疗法因此，为了设计新的和有效的策略以更好地治疗和/或预防为了了解耳生物和OM，有必要了解生物膜的生物学，包括其独特的生物化学特性，和蛋白质组组成，以及如何破坏这些结构来介导治疗治愈通过一系列三个高度综合的具体目标的成功实施，我们将扩大我们的实验室越来越多的文献奠定了坚实的基础，这些文献表明，我们可以针对一个家庭，细菌DNA结合蛋白（IHF和HU），对稳定存在的细胞外DNA（eDNA）至关重要在NTHI生物膜内以在体外和体内减少或根除该结构。在这里，我们现在将确定并在IHF和HU中表征最佳治疗抗原靶点，重点关注特异性功能域我们还将确定IHF和HU的释放动力学和可用性 NTHI eDNA-DNABII依赖性细胞外基质中的亚基，以鉴定最佳的干预的治疗窗口。此外，我们将确定使用生物膜聚焦，表位靶向的单克隆抗体及其混合物耳炎和中耳炎。这些后面的研究将首先使用单种生物膜在体外进行，以及混合耳病原体病因的那些，以更好地反映临床状况。最后我们将使用灰鼠实验模型确定这种方法在体内的相对治疗效果， OM。龙猫代表了一个解剖学上合适的，强大的，可再生的和广泛的研究这种高度流行的儿科生物膜疾病的动物模型，在其中进行这些基本的临床前问题研究重要的是，虽然我们的疾病干预的主要目标是OM，因为NTHI导致许多生物膜相关的人类呼吸道疾病，这里提出的研究也可能提供一个设计更好的治疗气道其他部位疾病（如鼻窦）的实践基础鼻窦炎），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）。我们的具体目标是完美的与2020年健康人群（听力和其他感官或沟通障碍，ENT-VSL-2： “减少儿童和青少年的中耳炎”），以及2012-2016财年NIDCD战略计划，其中优先研究领域3 -改善诊断，治疗和预防，宣布了一项任务，“发展预防和治疗生物膜的疗法。”