Pathogenic role of IL-17 response in Streptococcus pneumoniae nasopharyngeal pathogenesis during an influenza virus co-infection

流感病毒合并感染期间肺炎链球菌鼻咽部发病机制中IL-17反应的致病作用

• 批准号: 10064127
• 负责人: Nadeem Khan
• 金额: $ 35.71万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-03 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064127
• 关键词: Adoptive Transfer; Adult; Age; Air; Antibodies; Bacteria; Blood; Blood Circulation; Cell Culture Techniques; Cells; Child; Data; Development; Disease; Epithelial; Epithelial Cells; Flow Cytometry; Future; Gene Expression Profile; Generations; Genetic Transcription; Human; IL17 gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; Interleukin-17; Intervention; Invaded; Knock-out; Knockout Mice; Liquid substance; Lung; Lymphoid Cell; Mediating; Medical; Meningitis; Modeling; Mus; Nasopharynx; Otitis Media; Pathogenesis; Pathogenicity; Phenotype; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Population; Prevention; Rag1 Mouse; Receptor Signaling; Regulation; Reporter; Research; Research Proposals; Resistance; Risk Factors; Role; Sepsis; Serotyping; Signal Transduction; Sinusitis; Source; Sterility; Streptococcus pneumoniae; Structure; Surface; Testing; Tissues; Vaccines; base; burden of illness; clinically significant; co-infection; experimental study; improved; in vivo; influenzavirus; loss of function; novel; pathogen; pathogenic bacteria; prevent; receptor; respiratory; response; success; therapy design; transcription factor; transcriptome; vaccine access

ABSTRACT Streptococcus pneumoniae (Spn) is a major respiratory bacterial pathogen, asymptomatically carried (colonization) in the nasopharynx, by a significant proportion of the human population (children and adults). Colonization is a precursor to Spn disease (pneumonia, sinusitis, otitis media, sepsis, meningitis) which accounts for a significant disease burden in humans. Despite a decline in the overall Spn disease burden caused by currently available vaccines, Spn diseases continue to occur and remain a significant medical problem. Nasopharyngeal colonization is a precursor for Spn diseases, and co-infection with an influenza virus is a significant risk factor for the development of Spn disease. The influenza virus promotes damaging inflammation in the nasopharynx, which leads to bacterial outgrowth and dissemination of Spn bacteria to sterile tissues (lungs, blood) to establish disease. However, the mechanisms implicated in the damaging inflammation and consequent transition of Spn colonization into the disease, remain poorly understood. We developed an Spn-Influenza A Virus (IAV) co-infection model of Spn disease, by introducing IAV in Spn colonized mice. Our nasopharyngeal co-infection model mimics the natural pathogenesis of Spn involving the transition of Spn colonization to disease. Our preliminary data shows that the infection of Spn (serotype 6A) colonized mice with IAV elicits a robust IL-17A response that promotes hyper-inflammation in the NP, which leads to bacterial dissemination (lungs/blood) and the development of Spn disease. An antibody-mediated neutralization of IL-17A mitigated inflammation in the nasopharynx, results in a reduced Spn burden in the NP and blood with improved survival. Additionally, we show that innate lymphoid cells 3 (ILC3s) are a potential source of the pathogenic IL-17 response in our co-infection model of Spn disease. This data highlights the previously unrecognized role of the IL-17 response as a contributor to nasopharyngeal hyper-inflammation and the promotion of Spn disease in a co-infection setting with influenza virus. Based on our presented preliminary data, this 5-year research proposal hypothesizes that “influenza-induced IL- 17 response leads to the development of a pro-inflammatory immune phenotype, epithelial inflammation, and compromised barrier response in the NP, resulting in the dissemination/invasion of Spn bacteria from the NP into the lungs/bloodstream to establish Spn disease”. This hypothesis will be tested in three structured aims that will describe the mechanisms operating at multiple levels from the generation of the pathogenic IL-17 response and the role of IL-17 receptor signaling in epithelial inflammation and airway-barrier integrity, leading to the development of Spn disease. The findings will be central to designing interventions for translational utility, in the future.

抽象的 肺炎链球菌（SPN）是主要呼吸细菌病原体，不对称携带 （殖民化）在鼻咽中，由大部分人口（儿童和成人）中的很大一部分。 殖民化是SPN疾病（肺炎，鼻窦炎，中耳炎，败血症，脑膜炎）的先驱 对于人类的重大疾病伯恩。尽管总体SPN疾病伯恩引起的总体SPN疾病有所下降 当前可用的疫苗，SPN疾病继续发生，并且仍然是一个重大的医疗问题。 鼻咽定植是SPN疾病的前体，与影响病毒共同感染是一种 SPN疾病发展的重要危险因素。影响病毒促进了损害感染 在鼻咽中，导致细菌的生长和SPN细菌传播到无菌组织（肺， 血液）建立疾病。但是，在破坏性炎症中实施的机制以及随之而来的 SPN定殖向该疾病的过渡仍然很少了解。 我们通过在SPN中引入IAV的SPN-Influenza A病毒（IAV）的SPN疾病感染模型 殖民小鼠。我们的鼻咽共感染模型模仿SPN的自然发病机理涉及 SPN定植向疾病的过渡。我们的初步数据表明SPN的感染（血清型6a） 用IAV殖民的小鼠引起了鲁棒的IL-17A反应，该反应促进了NP中的过度炎症，该反应 导致细菌传播（肺/血液）和SPN疾病的发展。抗体介导的 IL-17A减轻鼻咽注射的中和，导致NP的SPN燃烧降低 和血液具有改善的生存。此外，我们表明先天淋巴样细胞3（ILC3）是一个潜力 在我们的SPN疾病的共感染模型中，致病性IL-17反应的来源。此数据突出显示 IL-17响应以前未认识到的作用是鼻咽性超炎和 在与影响力病毒的共感染环境中促进SPN疾病。 根据我们提出的初步数据，这项为期5年的研究建议假设“流感引起的IL- 17反应导致促炎性免疫型，上皮炎症和 NP中的屏障响应受损，导致SPN细菌从NP传播/侵袭 进入肺/血液以建立SPN疾病”。该假设将以三个结构化的目的进行检验 将描述从致病性IL-17反应的产生中以多个级别运行的机制 IL-17受体信号传导在上皮注入和气道屏障完整性中的作用，导致 SPN疾病的发展。这些发现将是为翻译实用程序设计干预措施的核心 未来。