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: 10531541
• 负责人: Nadeem Khan
• 金额: $ 38.11万
• 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/10531541
• 关键词: Adoptive Transfer; Adult; Age; Air; Antibodies; Bacteria; Blood; Blood Circulation; Cell Culture Techniques; Cells; Child; Data; Development; Disease; Epithelial Cells; Epithelium; Flow Cytometry; Future; Gene Expression Profile; Generations; Genetic Transcription; Human; IL17 gene; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza; Influenza A virus; 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; Sorting; Source; Sterility; Streptococcus pneumoniae; Structure; Surface; Testing; Tissues; Vaccines; 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(Spn)是一种主要的呼吸道细菌病原体，无症状携带 (殖民)在鼻咽部，相当大比例的人口(儿童和成人)。 定植是脊柱病(肺炎、鼻窦炎、中耳炎、败血症、脑膜炎)的前驱症状 对人类造成重大疾病负担。尽管由以下原因造成的脊柱疾病总体负担有所下降 尽管目前已有疫苗，但Spn疾病仍在继续发生，并仍然是一个重大的医疗问题。 鼻咽定植是脊柱疾病的先兆，与流感病毒混合感染是一种 脊椎病发生的重要危险因素。流感病毒促进破坏性炎症 在鼻咽中，这导致细菌生长并将Spn细菌传播到无菌组织(肺， 血液)以确定疾病。然而，导致破坏性炎症和随之而来的 Spn定植转化为该病的过程仍然知之甚少。 我们通过在Spn中引入甲型流感病毒(IAV)，建立了Spn病的IAV混合感染模型 被殖民的老鼠。我们的鼻咽联合感染模型模拟了Spn的自然发病机制，涉及 脊柱定植向疾病的转变。我们的初步数据显示，Spn(6A型)的感染 携带IAV的定植小鼠引起强烈的IL-17A反应，促进NP的过度炎症，这 导致细菌传播(肺/血)和脊柱疾病的发展。一种抗体介导的 IL-17A的中和减轻了鼻咽部的炎症，导致NP的Spn负担减轻 以及存活率更高的血液。此外，我们还证明了先天淋巴样细胞3(ILC3)是一种潜在的 我们的Spn病混合感染模型中致病性IL-17反应的来源。这一数据突显了 IL-17反应在鼻咽高炎症中的作用未被认识 在与流感病毒混合感染的情况下促进Spn疾病的发生。 根据我们提供的初步数据，这项为期5年的研究方案假设：“流感诱导的IL-1- 17反应导致促炎免疫表型、上皮炎症和 NP中的屏障反应受损，导致Spn细菌从NP传播/入侵 进入肺部/血流，以建立脊柱疾病“。这一假设将在三个结构化目标中得到检验 将描述从产生致病的IL-17反应起在多个水平上运行的机制 IL-17受体信号在上皮炎症和呼吸道屏障完整性中的作用，导致 脊椎病的发展。这些发现将是设计翻译效用干预措施的核心，在 未来。