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

项目摘要 该建议解决了细菌性中耳炎（OM）的临床重要问题，这是医院感染的主要来源。 幼儿可预防的听力损失和最常见的抗生素诊断 这个年龄段的处方。肺炎链球菌是两种最常见的细菌性肺炎的原因之一， OM，由细菌从鼻咽侵入中耳引起。尽管广泛的疫苗 use，S.肺炎仍然是一种重要的OM病原体，表明需要新的治疗方法。 然而，关于导致细菌OM的宿主因素仍然存在很大的知识缺口 发病机制为了解决这些知识缺口，我们开发了一种新的S.肺炎 侵入中耳。该模型是基于病毒合并感染增加OM的临床观察 在儿童和小鼠中，S.肺炎侵袭。我们发现连续注射病毒 dsRNA类似物poly（I：C）足以促进S.肺炎侵袭中耳。Poly（I：C）诱导 I型干扰素（IFN）的产生，其有助于S.其他组织中的肺炎存活率。在 第一个目的，我们提出了I型干扰素增强S的假设。肺炎存活在中耳。i型 干扰素可以诱导抗炎细胞因子IL-10的产生，我们最近证实了这一点。 抑制对S的保护。肺炎在肺部感染。在这里，我们研究IL-10是否 poly（I：C）处理的小鼠中的信号传导增强S.肺炎生存中耳侵犯，以及 IL-10对中耳炎的影响。总之，这些实验将决定I型糖尿病 IFN对S.肺炎OM发病机制。在第二个目标中，我们研究了 宿主微生物组接受抗生素治疗的儿童易患复发性细菌性OM， 包括s.肺炎杆菌比许多非致病性（non-pathogenic）物种对抗生素更耐药。在 初步数据，我们发现抗生素治疗的小鼠增加了S。肺炎侵袭和减少 中性粒细胞向中耳募集。我们研究了微生物组依赖性中性粒细胞 招募早期清除S.肺炎后中耳侵入。在上呼吸道， 下一代测序鉴定了流行的棒状杆菌， 与儿童OM相关，表明潜在的保护作用。在这里，我们确定是否 棒状杆菌提高了对S.肺炎OM在我们的小鼠模型中作为第一步， 为儿童OM开发新的基于益生菌的方法。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，以改善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.