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; 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（由适用提供）：耳炎培养基（OM）是最常见的儿童细菌感染和听力损失的主要原因。它仍然是一个重大的健康问题，也是一个实质性的社会经济伯恩伯恩（Burnen）。肺炎链球菌（SP）是引起OM的主要革兰氏阳性细菌。当前的疫苗对OM和不适当的抗生素使用的影响有限，增加了抗生素耐药性。迄今为止，由于对SP发病机理的了解不足，还没有有效的非抗生素治疗剂可用于OM。适当的先天免疫响应对于儿童的宿主防御至关重要。但是，如果不受控制，过度的炎症反应通常会导致免疫病理学和中耳功能受损。那就是必须严格控制先天的炎症反应。但是，关键的调节剂和潜在机制仍然在很大程度上未知。我们的长期目标是了解SP诱导的OM发病机理中对先天性炎症和宿主防御反应的严格控制的基础机制，并发展了新型的非抗生素疗法。我们先前表明，MAP激酶ERK1阳性地介导病理反应，而去泛素酶CYLD和磷酸酶MKP-1充当病理反应的关键负调节剂。这就是我们假设CYLD和MKP-1可以通过去泛素化和去磷酸化来抑制ERK1来严格调节SP诱导的感染和宿主防御，并且上调CYLD和MKP-1可能代表了理想和新颖的治疗策略，以抑制过量感染并维持适当的宿主防御。实际上，我们的初步研究表明，CYLD和MKP-1是SP诱导感染的负调节剂，但可能通过抑制ERK1的抗微生物β-德防御素的阳性调节剂。令人兴奋的是，全身性和CPE介导的葡萄肽氨酸的耳端给药，一种现有的神经系统疾病药物，抑制感染，改善的听力损失以及增强的β-防发素诱导以及可能通过上调的CYLD和MKP-1的上调。 vinpocetine还抑制了慢性OM模型中的注射和改善的听力。因此，这些令人兴奋的初步数据为我们奠定了坚实的基础，以进一步研究SP诱导的先天炎症和宿主防御反应的严格调节的机制，并评估vinpocetine在OM中的治疗潜力。我们的具体目的是：目标1。确定SP诱导的先天炎症和宿主防御反应如何通过抑制ERK1严格控制。 AIM 2。确定长葡萄氨酸如何抑制SP诱导的炎症并增强宿主防御。 AIM 3。确定vinpocetine口服和耳尾剂在抑制SP诱导的感染并增强急性和慢性OM动物模型中的宿主防御方面的治疗潜力。总体而言，拟议的研究将提高我们对SP诱导的OM分子发病机理的理解，并可能导致新型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SP诱导的OM（影响和意义）的宿主防御。