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

影响肺炎链球菌从鼻咽部侵入后中耳早期清除的宿主因素

• 批准号: 10358434
• 负责人: Sarah E Clark
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358434
• 关键词: 6 year old; Address; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Bacterial Proteins; Child; Clinical; Clinical Management; Corynebacterium; Data; Defect; Development; Diagnosis; Disease; Double-Stranded RNA; Flow Cytometry; Goals; Growth; Histology; Hospitals; IFNAR1 gene; IL8RB gene; Image; Immune; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Injections; Innate Immune Response; Integration Host Factors; Interferon Type I; Interferon-alpha; Interferons; Interleukin-10; Interleukin-8B Receptor; Knockout Mice; Knowledge; Lung; Measures; Mediating; Modeling; Mus; Myeloid Cells; Nasopharynx; Neutrophil Infiltration; Otitis Media; Pathogenesis; Pathway interactions; Pneumococcal Infections; Population; Predisposition; Probiotics; Process; Production; Proteins; Recurrence; Reporting; Resistance; Risk; Role; Signal Transduction; Site; Source; Stimulus; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Tissues; Upper respiratory tract; Vaccines; Viral; Virulence; Virus Replication; Visit; Wild Type Mouse; age group; analog; base; cell type; chemokine receptor; childhood hearing loss; clinically significant; co-infection; cytokine; economic impact; experimental study; hearing impairment; host microbiome; immune activation; improved; infection burden; microbiome; middle ear; mouse model; neutrophil; next generation sequencing; novel; novel therapeutic intervention; pathogen; pathogenic bacteria; pathogenic virus; prevent; protein expression; recruit; recurrent infection; respiratory; response; therapeutic target

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.

项目摘要 该提议解决了细菌性中耳炎（OM）的临床意义问题，这是医院的主要来源 幼儿的访问和可预防的听力损失和抗生素的最常见诊断 该年龄段的处方。肺炎链球菌是细菌的两个最常见原因之一 OM是由细菌从鼻咽到中耳的细菌侵袭引起的。尽管疫苗广泛 使用，肺炎链球菌仍然是一种重要的OM病原体，表明需要采用新的治疗方法。 但是，关于有助于细菌OM的宿主因素仍然存在很大的知识差距 发病。为了解决这些知识差距，我们开发了肺炎链球菌的新鼠标模型 入侵中耳。该模型基于临床观察结果，即病毒共感染增加了OM 儿童的风险和小鼠促进肺炎链球菌侵袭。我们发现病毒的连续给药 DSRNA模拟聚（I：C）足以促进肺炎链球菌侵袭中耳。 poly（i：c）诱导 I型干扰素（IFN）的产生，有助于其他组织中的肺炎链球菌存活。在 首先，我们解决了I型IFNS增强中耳肺炎链球菌存活的假设。类型I。 IFN可以诱导抗炎细胞因子IL-10的产生，我们最近证明了这一点 抑制肺中肺炎链球菌感染的保护。在这里，我们调查IL-10是否 Poly（I：C）处理的小鼠中的信号传导增强了中耳入侵后的肺炎链球菌存活，以及 IL-10对中耳炎症的影响。这些实验将共同确定I型是否 IFN有助于肺炎链球菌的发病机理。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容易复发细菌OM和病原体 包括肺炎链球菌对抗生素具有比许多共同（非致病性）物种更具抵抗力。在 初步数据，我们发现抗生素治疗的小鼠已增加了肺炎链球菌侵袭并减少 中性粒细胞招募到中耳。我们研究了微生物组依赖性中性粒细胞的重要性 中耳入侵后，招募肺炎链球菌。在上呼吸道， 通过下一代测序鉴定出普遍的共生菌群是负面的 与儿童中的OM相关，表明潜在的保护作用。在这里，我们确定是否 Corynebacterium在我们的鼠标模型中改善了针对肺炎链球菌的保护，作为迈向的第一步 在儿童中为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/或益生菌策略来增加OM疾病的负担。