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: 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
• 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

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 我们对中耳炎的发病机理（OM）的理解最近取得了巨大进步 由于不可能的嗜血杆菌影响（NTHI）。重要的是，我们已经意识到 生物膜在两种后的骨术耳状以及nthi-的慢性和复发性中发挥作用 诱导的OM。生物膜内居住的细菌构成了免疫力影响的巨大障碍 抗生素疗法。因此，为了设计新颖有效的策略，以更好地治疗和/或阻止 Otorrhea和Om，有必要了解生物膜的生物学，包括它们独特的生化 和蛋白质组学组成，以及如何破坏这些结构以介导治疗 '治愈'。通过成功进行一系列高度集成的特定目标，我们将扩展 我们实验室越来越多的文献的坚实基础，表明我们可以针对一个家庭 细菌DNA结合蛋白（IHF和HU）对于稳定存在的细胞外DNA（EDNA）至关重要 在NTHI生物膜内，以减少或根除体外和体内结构。在这里，我们现在将确定 并表征IHF和HU中最佳的治疗性抗原靶标 功能域。我们还将确定发行的动力学和IHF和HU的可用性 nthi edna-dnabii依赖性细胞外基质中的亚基，以识别最佳 干预的治疗窗口。此外，我们将确定使用以生物膜为中心的治疗价值 靶向表位的单克隆抗体及其鸡尾酒可解决与慢性相关的生物膜 耳开正性和中耳炎。这些后来的研究将首先使用两个单种生物膜在体外进行，即 以及混合性耳病病学的混合病因，以更好地反映临床状况。最后，我们会的 使用实验模型，确定这种方法在体内的相对治疗效率 om。龙猫代表一个解剖学上适当的，可靠的，可重复的和广泛研究的 这种高度普遍的小儿生物膜疾病的动物模型，其中进行这些必不可少的临床前 研究。重要的是，虽然我们的主要疾病干预目标是OM，因为NTHI导致许多 人类呼吸道与生物膜相关疾病，此处提出的研究也可能提供 设计更好实践以治疗气道其他部位（如鼻窦）（慢性）的疾病的基础 鼻孔炎），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） 肺（COPD，早期CF，社区获得了肺炎）。我们的具体目标是完美的 与2020年健康的人保持一致（听力和其他感觉或沟通障碍，ENT-VSL-2： “减少儿童和青少年的中耳炎”）和NIDCD战略计划2012-2016，其中 优先研究领域3 - 改善诊断，治疗和预防，宣布“发展 预防和治疗生物膜的疗法。”