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: 10543317
• 负责人: Nadeem Khan
• 金额: $ 39万
• 依托单位: UNIVERSITY OF FLORIDA
• 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/10543317
• 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.

摘要 肺炎链球菌（Streptococcus pneumoniae，Spn）是一种主要的呼吸道病原菌，无症状携带 在鼻咽中，由相当大比例的人群（儿童和成年人）引起（定殖）。 定植是Spn疾病（肺炎、鼻窦炎、中耳炎、败血症、脑膜炎）的前兆， 给人类带来巨大的疾病负担。尽管由以下因素引起的总体Spn疾病负担有所下降， 尽管目前已有疫苗，但SPN疾病仍在发生，并且仍然是一个重要的医学问题。 鼻咽定殖是Spn疾病的前兆，并且与流感病毒的共感染是Spn疾病的先兆。 这是发生Spn疾病的重要危险因素。流感病毒促进破坏性炎症 这导致细菌生长和Spn细菌向无菌组织（肺， 血液），以建立疾病。然而，与破坏性炎症及其后果有关的机制 对于Spn定植向疾病的转变，仍然知之甚少。 本研究通过将甲型流感病毒（Influenza A Virus，IAV）引入Spn，建立了Spn病的IAV共感染模型 殖民小鼠我们的鼻咽部共感染模型模拟了Spn的自然发病机制， Spn定植向疾病的转变。我们的初步数据表明，Spn（血清型6A）感染 用IAV定殖的小鼠激发了强烈的IL-17 A应答，该应答促进NP中的过度炎症， 导致细菌传播（肺/血液）和Spn疾病的发展。抗体介导的 IL-17 A的中和减轻了鼻咽中的炎症，导致NP中Spn负荷降低 和血液，提高了生存率。此外，我们表明先天淋巴样细胞3（ILC 3）是一种潜在的 在我们的Spn疾病的共感染模型中致病性IL-17应答的来源。这些数据突出了 IL-17应答作为鼻咽过度炎症的贡献者的先前未被认识的作用， 在与流感病毒共感染的情况下促进SPN疾病。 根据我们提供的初步数据，这项为期5年的研究计划假设“流感诱导的IL-10可能与流感病毒感染有关。 17应答导致促炎性免疫表型、上皮炎症和 NP中的屏障反应受损，导致Spn细菌从NP传播/侵入 进入肺部/血液以建立SPN疾病”。这一假设将在三个结构化目标中得到检验， 将描述致病性IL-17应答产生的多个水平的机制 以及IL-17受体信号在上皮炎症和气道屏障完整性中的作用，导致 Spn疾病的发展。这些发现将是设计翻译效用干预措施的核心， 未来