Pathogenesis of pneumococcal otitis media

 描述（由申请人提供）：中耳炎（OM）是最常见的儿童细菌感染，也是导致听力损失的主要原因。它仍然是一个重大的健康问题和巨大的社会经济负担。S.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，不适当的抗生素使用增加了耐药性。迄今为止，由于对Sp发病机制的认识不足，没有有效的非抗生素治疗药物可用于OM。适当的先天免疫应答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导致免疫病理学和中耳功能受损。因此，必须严格控制先天性炎症反应。然而，关键的监管机构和基本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OM发病机制中先天性炎症和宿主防御反应的分子机制，并开发新的非抗生素治疗方法。我们以前发现，MAP激酶ERK 1正介导的病理反应，而去泛素化酶CYLD和磷酸酶MKP-1作为关键的病理反应的负调节。因此，我们推测CYLD和MKP-1可能通过去泛素化和去磷酸化抑制ERK 1来密切调节SP诱导的炎症和宿主防御，并且上调CYLD和MKP-1可能代表一种理想的和新的治疗策略，以抑制过度炎症并维持适当的宿主防御。事实上，我们的初步研究表明，CYLD和MKP-1对SP诱导的炎症起负调节作用，但对抗菌性β-防御素起正调节作用，可能通过抑制ERK 1;令人兴奋的是，全身和CPE介导的耳局部给予长春新碱（一种现有的神经系统疾病药物），抑制了炎症，通过上调CYLD和MKP-1，改善听力损失和增强β-防御素诱导和细菌清除。长春新碱还抑制炎症，并改善听力在一个良好的慢性OM模型。因此，这些令人兴奋的初步数据为我们进一步研究SP诱导的先天性炎症和宿主防御反应的紧密调节机制以及评估长春新碱在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ERK 1来严格控制SP诱导的先天性炎症和宿主防御反应。目标二。确定长春新碱如何抑制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，确定口服和耳局部施用长春新碱在抑制SP诱导的炎症和增强宿主防御方面的治疗潜力。总体而言，拟议的研究将推进我们对SP诱导的OM的分子发病机制的理解，并可能导致新的治疗策略，以抑制过度活跃的炎症，改善中耳听力功能，增强宿主对SP诱导的OM的防御（影响与意义）。

 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).