Pathogenesis of pneumococcal otitis media

描述（申请人提供）：中耳炎（OM）是儿童最常见的细菌感染，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的主要革兰氏阳性细菌。目前的疫苗对OM的影响有限，不适当使用抗生素会增加抗生素耐药性。迄今为止，由于对Sp的发病机制了解不足，没有有效的非抗生素治疗药物可用于OM。适当的先天免疫反应对儿童宿主防御至关重要。然而，如果不加以控制，过度的炎症反应往往导致免疫病理和中耳功能受损。因此，必须严格控制先天炎症反应。然而，主要的监管机构和潜在的机制在很大程度上仍然未知。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，并开发新的非抗生素治疗方法。我们之前的研究表明，MAP激酶ERK1积极介导病理反应，而去泛素酶CYLD和磷酸酶MKP-1则是病理反应的关键负调控因子。因此，我们假设CYLD和MKP-1可能通过去泛素化和去磷酸化ERK1来抑制sp诱导的炎症和宿主防御，而上调CYLD和MKP-1可能是抑制过度炎症和维持适当宿主防御的理想和新颖的治疗策略。事实上，我们的初步研究表明，CYLD和MKP-1作为sp诱导炎症的负调节因子，但作为抗菌ß-防御素的正调节因子，可能通过抑制ERK1；令人兴奋的是，全身和cpe介导的耳外给药Vinpocetine（一种现有的神经系统疾病药物）抑制炎症，改善听力损失，增强ß-防御素诱导和细菌清除，可能是通过上调CYLD和MKP-1。长春西汀还能抑制慢性OM模型的炎症和改善听力。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控机制以及评估长春西汀对OM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sp诱导的先天炎症和宿主防御反应是如何通过抑制ERK1来严格控制的。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。确定口服和耳外用长春西汀在急性和慢性OM动物模型中抑制sp诱导炎症和增强宿主防御的治疗潜力。综上所述，本研究将促进我们对sp诱导OM的分子发病机制的理解，并可能为抑制过度活跃炎症、改善中耳听力功能和增强sp诱导OM的宿主防御提供新的治疗策略（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).