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.”

项目总结 最近，我们对中耳炎(OM)发病机制的了解有了很大的进步。 由于非分型流感嗜血杆菌(NTHI)。值得注意的是，我们已经开始意识到 生物膜在鼓室造孔术后耳漏以及NTHI的慢性和复发中都起作用。 诱导性OM。栖息在生物膜内的细菌对免疫效应器和 抗生素疗法。因此，为了设计新的有效策略来更好地治疗和/或预防 对于耳漏和OM，有必要了解生物膜的生物学，包括它们独特的生化 和蛋白质组组成，以及一个人如何破坏这些结构来调节治疗 “治愈”。通过成功地实现三个高度整合的具体目标，我们将扩大 来自我们实验室的越来越多的文献表明我们可以针对一个家庭提供坚实的基础 细菌DNA结合蛋白(IHF和HU)是稳定细胞外DNA(EDNA)的关键 在体外和体内，NTHI生物膜中都可以减少或消除这种结构。在这里，我们现在将确定 并确定IHF和HU内最好的治疗性抗原靶点，重点是特异性 功能域。我们还将测定IHF和HU的释放动力学和可利用性 NTHI Edna-DNABII依赖的细胞外基质内的亚基，以确定最佳的 干预的治疗窗口。此外，我们将确定使用生物膜聚焦的治疗价值， 表位靶向的单抗及其鸡尾酒，以解析与慢性阻塞性肺疾病相关的生物膜 耳漏和中耳炎。这些后一种研究将首先使用两种单种生物膜在体外进行， 以及耳科混合病原体的病原学，以更好地反映临床情况。最后，我们会 在活体实验中，使用龙猫模型确定这种方法的相对治疗效果。 奥姆。龙猫代表着一种解剖上合适的、健壮的、可复制的和被广泛研究的 这种高度流行的儿科生物膜病的动物模型，在其中进行这些必要的临床前研究 学习。重要的是，尽管我们疾病干预的主要目标是OM，因为NTHI导致了许多 对于人类呼吸道的生物膜相关疾病，这里提出的研究也可能提供 设计更好的做法来治疗呼吸道其他部分的疾病的基础，如鼻窦(慢性 鼻窦炎)、扁桃体和腺样体(扁桃体炎、腺体炎)、支气管炎(慢性咳嗽和支气管炎) 肺(慢性阻塞性肺疾病、早期慢性阻塞性肺疾病、社区获得性肺炎)。我们的具体目标是完美的 与2020年健康人(听力和其他感觉或沟通障碍，ENT-VSL-2： “减少儿童和青少年中耳炎”)，以及NIDCD 2012-2016财年战略计划，其中 优先研究领域3--改善诊断、治疗和预防，宣布任务是“发展 预防和治疗生物被膜的疗法。“