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重大的社会经济负担。肺炎链球菌是引起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抗生素的耐药性。到目前为止，由于对Sp的发病机制缺乏了解，目前还没有有效的非抗生素治疗OM的药物。适当的先天免疫反应对儿童的宿主防御至关重要。然而，如果不加控制，过度的炎症反应往往会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，关键监管机构和潜在机制在很大程度上仍不为人所知。我们的长期目标是了解在SP诱导的OM发病机制中严密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。我们先前的研究表明，MAP激酶ERK1正向介导病理反应，而去泛素酶、CyLD和磷酸酶MKP-1则是病理反应的主要负调控因子。因此，我们推测，CyLD和MKP-1可能通过抑制ERK1的去泛素化和去磷酸化来密切调控Sp诱导的炎症和宿主防御，上调CyLD和MKP-1可能是抑制过度炎症和维持适当的宿主防御的一种理想的新的治疗策略。事实上，我们的初步研究表明，CyLD和MKP-1对Sp诱导的炎症起到负面调节作用，但对抗菌素-防御素起积极调节作用，可能是通过抑制ERK1；令人兴奋的是，全身和CPE介导的耳部给药长春西汀，一种现有的治疗神经系统疾病的药物，通过上调CyLD和MKP-1可能抑制炎症，改善听力损失，增强？防御素诱导和细菌清除。长春西汀还能抑制炎症，改善慢性OM模型的听力。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密调控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：目的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而受到严格控制的。目的2.确定长春西汀如何抑制Sp诱导的炎症和增强宿主防御。目的3.观察长春西汀对急、慢性OM动物模型的抗炎作用和增强宿主防御作用。总之，这些研究将促进我们对Sp诱导的OM的分子发病机制的理解，并可能导致抑制Sp诱导的OM的过度炎症反应、改善中耳听力和增强宿主防御的新的治疗策略(Impact&Signality)。

 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).