Host factors influencing early clearance of Streptococcus pneumoniae from the middle ear following invasion from the nasopharynx

项目摘要 这项建议解决了细菌性中耳炎(OM)的临床重要问题，这是医院的一个主要来源 幼儿就诊和可预防的听力损失与抗生素最常见的诊断 这一年龄段的处方。肺炎链球菌是引起细菌的两种最常见的原因之一 OM，它是由细菌从鼻咽到中耳的入侵造成的。尽管疫苗广泛使用 使用，肺炎链球菌仍然是一种重要的OM病原体，表明需要新的治疗方法。 然而，关于导致细菌性OM的寄主因素，仍然存在很大的知识差距 发病机制。为了解决这些知识差距，我们开发了一种新的肺炎链球菌小鼠模型。 侵犯中耳。该模型建立在病毒合并感染增加OM的临床观察基础上 在儿童中的风险，在老鼠中促进肺炎链球菌的侵袭。我们发现对病毒的连续注射 DsRNA类似物Poly(I：C)足以促进肺炎链球菌向中耳的侵袭。Poly(I：C)诱导 I型干扰素(IFN)的产生，有助于肺炎链球菌在其他组织中的存活。在 首先，我们提出了I型干扰素增强肺炎链球菌在中耳存活的假说。第I类 干扰素可以诱导抗炎细胞因子IL-10的产生，这是我们最近证明的 抑制对肺部肺炎链球菌感染的保护。在这里，我们调查IL-10是否 聚(I：C)处理的小鼠在中耳入侵后增强肺炎链球菌存活的信号，以及 IL-10对中耳炎症的影响加在一起，这些实验将决定I型 干扰素参与肺炎链球菌OM的致病过程。在第二个目标中，我们调查了 寄主微生物组。接受抗生素治疗的儿童易患复发的细菌性OM和病原体 包括肺炎链球菌在内的许多共生(非致病)物种对抗生素的抗药性更强。在……里面 初步数据，我们发现抗生素处理的小鼠增加了肺炎链球菌的侵袭并减少了 中性粒细胞重新聚集到中耳。我们调查了依赖微生物组的中性粒细胞的重要性 中耳侵袭后早期清除肺炎链球菌的招募。在上呼吸道， 流行的共生棒状杆菌经下一代测序鉴定为阴性 与儿童的OM相关，表明了潜在的保护作用。在这里，我们确定是否 棒状杆菌在我们的小鼠模型中提高了对肺炎链球菌OM的保护作用，作为迈向 开发以益生菌为基础的治疗儿童OM的新方法。这些研究的长期目标是 开发新的免疫疗法和/或益生菌策略，以减轻OM疾病的负担。

Project Summary This proposal addresses the clinically significant issue of bacterial otitis media (OM), a major source of hospital visits and preventable hearing loss in young children and the most common diagnosis for antibiotic prescriptions in this age group. Streptococcus pneumoniae is one of the two most common causes of bacterial OM, which results from bacterial invasion from the nasopharynx to the middle ear. Despite widespread vaccine use, S. pneumoniae remains a significant OM pathogen, indicating the need for new therapeutic approaches. However, large knowledge gaps remain regarding the host factors which contribute to bacterial OM pathogenesis. To address these knowledge gaps, we developed a new mouse model of S. pneumoniae invasion to the middle ear. This model is based on the clinical observation that viral co-infection increases OM risk in children, and in mice promotes S. pneumoniae invasion. We find that serial administration of the viral dsRNA analog poly(I:C) is sufficient to promote S. pneumoniae invasion to the middle ear. Poly(I:C) induces the production of type I interferons (IFNs), which contribute to S. pneumoniae survival in other tissues. In the first Aim, we address the hypothesis that type I IFNs enhance S. pneumoniae survival in the middle ear. Type I IFNs can induce production of the anti-inflammatory cytokine IL-10, which we recently demonstrated suppresses protection against S. pneumoniae infection in the lung. Here, we investigate whether IL-10 signaling in poly(I:C) treated mice enhances S. pneumoniae survival following middle ear invasion, as well as the impact of IL-10 on middle ear inflammation. Together, these experiments will determine whether type I IFNs contribute to S. pneumoniae OM pathogenesis. In the second Aim, we investigate the importance of the host microbiome. Children treated with antibiotics are susceptible to recurrent bacterial OM, and pathogens including S. pneumoniae are more resistant to antibiotics than many commensal (non-pathogenic) species. In preliminary data, we find that antibiotic treated mice have increased S. pneumoniae invasion and reduced neutrophil recruitment to the middle ear. We investigate the importance of microbiome-dependent neutrophil recruitment for early clearance of S. pneumoniae following middle ear invasion. In the upper airway, the prevalent commensal Corynebacterium has been identified by next-generation sequencing as negatively correlated with OM in children, indicating a potentially protective role. Here, we determine whether Corynebacterium improves protection against S. pneumoniae OM in our mouse model as a first step toward developing new probiotic-based approaches for OM in children. The long-term goal of these studies is to develop novel immunotherapy and/or probiotic strategies to improve the burden of OM disease.