Pathogenesis of pneumococcal otitis media

肺炎球菌性中耳炎的发病机制

• 批准号: 9052165
• 负责人: Jian-Dong Li
• 金额: $ 32.19万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052165
• 关键词: Accounting; Acute; Animal Model; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Chemicals; Child; Childhood; Chronic; Clinical; Conductive hearing loss; DUSP1 gene; Data; Defensins; Deubiquitination; Enhancers; Foundations; Goals; Gram-Positive Bacteria; Health; Hearing; Homeostasis; Host Defense; Hydrogels; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; MAPK3 gene; MEKs; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Oral; Otitis Media; Otitis Media with Effusion; Pathogenesis; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Pneumococcal vaccine; Protein Dephosphorylation; Regulation; Role; Solid; Streptococcus pneumoniae; Therapeutic; Therapeutic Agents; Tympanic membrane; Ubiquitination; Vaccines; Visit; antimicrobial; base; beta-Defensins; cost; defense response; hearing impairment; immunopathology; improved; in vivo; innovation; middle ear; mouse model; nervous system disorder; novel; novel therapeutic intervention; novel therapeutics; response; socioeconomics; vinpocetine

 DESCRIPTION (provided by applicant): Otitis media (OM) is the most common childhood bacterial infection and the leading cause of hearing loss. It remains a major health problem and a substantial socioeconomic burden. S. pneumoniae (Sp) is a major gram-positive bacteria causing OM. Current vaccine has a limited impact on OM and inappropriate antibiotic use increased antibiotic-resistance. To date there have been no effective non-antibiotic therapeutic agents available for OM due to poor understanding of Sp pathogenesis. Appropriate innate immune response is critical for host defense in children. However, if uncontrolled, excessive inflammatory response often results in immunopathology and impaired function of middle ear. Thus, innate inflammatory response must be tightly controlled. However, the key regulators and the underlying mechanisms remain largely unknown. Our long-term goal is to understand the molecular mechanisms underlying the tight control of innate inflammatory & host defense response in Sp-induced OM pathogenesis and develop novel non-antibiotic therapeutics. We previously showed that MAP kinase ERK1 positively mediates pathological responses whereas deubiquitinase CYLD and phosphatase MKP-1 act as key negative regulators of pathological responses. Thus, we hypothesized that CYLD and MKP-1 may tightly regulate Sp-induced inflammation and host defense via inhibiting ERK1 by deubiquitinating and dephosphorylating it, and up-regulating CYLD and MKP-1 may represent an ideal and novel therapeutic strategy to inhibit excessive inflammation and maintain an appropriate host defense. Indeed, our preliminary studies demonstrate that CYLD and MKP-1 act as negative regulators for Sp-induced inflammation, but positive regulators for antimicrobial ß-defensin, likely via inhibiting ERK1; Excitingly, systemic and CPE-mediated ototopical administration of Vinpocetine, an existing drug for neurological diseases, suppressed inflammation, improved hearing loss and enhanced ß-defensin induction and bacterial clearance likely via up-regulating CYLD and MKP-1. Vinpocetine also inhibited inflammation and improved hearing in a well-established model of chronic OM. These exciting preliminary data have thus laid a solid foundation for us to further investigate the mechanisms underlying tight regulation of Sp-induced innate inflammatory & host defense responses and evaluate the therapeutic potential of Vinpocetine in OM. Our specific aims are: Aim 1. Determine how Sp-induced innate inflammatory & host defense responses are tightly controlled by inhibiting ERK1. Aim 2. Determine how Vinpocetine inhibits Sp-induced inflammation and enhances host defense. Aim 3. Determine the therapeutic potential of oral and ototopical administration of Vinpocetine in suppressing Sp-induced inflammation and enhancing host defense in acute and chronic OM animal models. Overall, the proposed studies will advance our understanding of molecular pathogenesis of Sp-induced OM and may lead to novel therapeutic strategy to suppress overactive inflammation, improve middle ear hearing function and enhance host defense for Sp-induced OM (Impact & Significance).

 描述（由申请人提供）：中耳炎（OM）是最常见的儿童细菌感染，也是听力损失的主要原因。它仍然是一个主要的健康问题和沉重的社会经济负担。肺炎链球菌 (Sp) 是引起 OM 的主要革兰氏阳性菌。目前的疫苗对 OM 的影响有限，并且不适当的抗生素使用会增加抗生素耐药性。迄今为止，由于对 Sp 发病机制了解甚少，尚无有效的非抗生素治疗剂可用于 OM。适当的先天免疫反应对于儿童的宿主防御至关重要。然而，如果不加以控制，过度的炎症反应往往会导致免疫病理学和中耳功能受损。因此，必须严格控制先天炎症反应。然而，关键监管机构和潜在机制仍然很大程度上未知。我们的长期目标是了解 Sp 诱导的 OM 发病机制中严格控制先天炎症和宿主防御反应的分子机制，并开发新型非抗生素疗法。我们之前表明，MAP 激酶 ERK1 正介导病理反应，而去泛素酶 CYLD 和磷酸酶 MKP-1 是病理反应的关键负调节因子。因此，我们假设CYLD和MKP-1可能通过去泛素化和去磷酸化抑制ERK1来严格调节Sp诱导的炎症和宿主防御，并且上调CYLD和MKP-1可能代表抑制过度炎症和维持适当宿主防御的理想且新颖的治疗策略。事实上，我们的初步研究表明，CYLD 和 MKP-1 作为 Sp 诱导的炎症的负调节剂，但作为抗菌 ß-防御素的正调节剂，可能通过抑制 ERK1 发挥作用；令人兴奋的是，长春西汀（一种治疗神经系统疾病的现有药物）的全身和 CPE 介导的耳局部给药，可能通过上调 CYLD 和 MKP-1 抑制炎症，改善听力损失并增强 ß-防御素诱导和细菌清除。在成熟的慢性 OM 模型中，长春西汀还能抑制炎症并改善听力。这些令人兴奋的初步数据为我们进一步研究 Sp 诱导的先天炎症和宿主防御反应的严格调节机制以及评估长春西汀在 OM 中的治疗潜力奠定了坚实的基础。我们的具体目标是： 目标 1. 确定如何通过抑制 ERK1 严格控制 Sp 诱导的先天炎症和宿主防御反应。目标 2. 确定长春西汀如何抑制 Sp 诱导的炎症并增强宿主防御。目标 3. 在急性和慢性 OM 动物模型中确定口服和耳局部给药长春西汀在抑制 Sp 诱导的炎症和增强宿主防御方面的治疗潜力。总体而言，拟议的研究将增进我们对 Sp 诱导的 OM 分子发病机制的理解，并可能产生新的治疗策略来抑制过度活跃的炎症、改善中耳听力功能并增强宿主对 Sp 诱导的 OM 的防御（影响和意义）。