Bacterial-driven immune suppression in the lung

肺部细菌驱动的免疫抑制

• 批准号: 10475452
• 负责人: Sarah E Clark
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475452
• 关键词: Acute; Address; Anti-Inflammatory Agents; Asthma; Automobile Driving; Bacteria; Bacterial Infections; Bacterial Proteins; Biological Assay; Bronchiectasis; Cells; Chronic Obstructive Airway Disease; Clinical; Cystic Fibrosis; Data; Dendritic Cells; Development; Environment; Future; Glucocorticoids; Goals; Health; Hemophilus influenza infection; Homeostasis; Immune; Immune System Diseases; Immune response; Immunity; Immunization; Immunosuppression; In Vitro; Infection; Inflammation; Interleukin-10; Interleukins; Licensing; Lipopolysaccharides; Listeria monocytogenes; Lower respiratory tract structure; Lung; Lung Inflammation; Lung diseases; Lung infections; Mediating; Modeling; Morbidity - disease rate; Mus; Myeloid Cell Activation; Myeloid Cells; NK Cell Activation; Natural Killer Cells; Nontypable Haemophilus influenza; Parasitic infection; Pathway interactions; Pneumococcal Infections; Population; Predisposition; Process; Production; Property; Proteins; Pulmonary Inflammation; Pulmonary Pathology; Resistance; Respiratory System; Respiratory Tract Infections; Secondary to; Signal Transduction; Sterility; Streptococcus pneumoniae; Systemic infection; Therapeutic; Virulence; Virus; Virus Diseases; Work; alternative treatment; cell type; cellular targeting; co-infection; cytokine; experimental study; foodborne; immunopathology; immunoregulation; insight; microbial; mortality; novel; novel strategies; novel therapeutic intervention; opportunistic pathogen; pathogen; pathogenic bacteria; pulmonary function; recruit; response; treatment strategy; tumor

PROJECT SUMMARY Lung inflammation during acute respiratory tract infection contributes to significant morbidity and mortality even after microbial clearance. The limited therapeutic options for lung inflammation beyond glucocorticoids highlights the need for alternative treatment strategies. The long-term goal of this work is to inform the development of novel therapeutic approaches for pulmonary disease. This proposal focuses on how bacterial stimulation of the immune-suppressive cytokine interleukin(IL)-10 influences lung homeostasis. In recent studies we identified a novel pathway for bacterial-induced immune suppression during systemic infection. We found that the foodborne bacterial pathogen Listeria monocytogenes (Lm) activates IL-10 production from natural killer (NK) cells, limiting host protection against infection. While NK cells contribute to clearance of viruses and tumors, they instead suppress resistance against some bacterial infections. In preliminary studies we found that NK cell-dependent IL-10 reduces protection against the respiratory tract opportunistic pathogen Streptococcus pneumoniae (Spn). Our data indicate that Spn induces IL-10 production by NK cells in the lung, and bacterial burdens are reduced in the absence of either NK cells or IL-10. For this proposal, I will determine how bacterial-induced NK cell IL-10 impacts lung immunity. My central hypothesis is that NK cell IL-10 limits bacterial clearance but is protective against lung inflammation. First, I examine whether Spn-induced NK cell IL-10 increases Spn persistence in the lung. Next, I investigate the impact of IL-10 signaling on discrete lung cell types and their contribution to host protection against Spn (Aim 1). These experiments will advance our understanding of the cellular targets of bacterial-mediated immune dysfunction in the lung. The lung environment is particularly susceptible to damage from inflammation, and the consequences of bacterial stimulation of IL-10 on lung immunopathology for sub-lethal Spn infection are not clear. In the second Aim of this proposal, I will first determine the impact of NK cell IL-10 on lung function and pathology during Spn infection. The discrete effects of IL-10 on bacterial clearance versus lung inflammation are difficult to separate. To address this, I will activate NK cell IL-10 in the absence of bacterial infection by instillation of bacterial proteins directly into the lung. Our studies with Lm found that a single virulence protein, p60, is sufficient to activate NK cell IL-10, and in preliminary data we show that instillation of p60 stimulates NK cell IL-10 production in the lung. We also found that Spn expresses a virulence protein with homology to p60 that activates lung NK cell IL-10 production in vitro. My proposed studies use these bacterial proteins to interrogate the impact of NK cell IL-10 on lung inflammation in the absence of infection, as well as susceptibility to secondary bacterial challenge (Aim 2). Together, these studies will contribute new insights into how respiratory tract bacteria influence pulmonary homeostasis.

项目概要 急性呼吸道感染期间的肺部炎症会导致显着的发病率和死亡率，甚至 微生物清除后。除糖皮质激素外，肺部炎症的治疗选择有限 强调需要替代治疗策略。这项工作的长期目标是让人们了解 开发肺部疾病的新治疗方法。该提案的重点是细菌如何 免疫抑制细胞因子白细胞介素 (IL)-10 的刺激会影响肺稳态。近来 在研究中，我们发现了全身感染期间细菌诱导的免疫抑制的新途径。我们 发现食源性细菌病原体单核细胞增生李斯特氏菌 (Lm) 可激活食源性细菌产生 IL-10 自然杀伤（NK）细胞，限制宿主免受感染的保护。虽然 NK 细胞有助于清除 病毒和肿瘤，它们反而会抑制对某些细菌感染的抵抗力。初步研究中 我们发现 NK 细胞依赖性 IL-10 降低了对呼吸道机会病原体的保护 肺炎链球菌 (Spn)。我们的数据表明 Spn 诱导肺部 NK 细胞产生 IL-10， 在没有 NK 细胞或 IL-10 的情况下，细菌负担也会减少。对于这个提案，我将确定 细菌诱导的 NK 细胞 IL-10 如何影响肺部免疫。我的中心假设是 NK 细胞 IL-10 限制 清除细菌，但可以预防肺部炎症。首先，我检查 Spn 是否诱导 NK 细胞 IL-10 增加 Spn 在肺部的持久性。接下来，我研究了 IL-10 信号传导对离散肺的影响 细胞类型及其对宿主针对 Spn 的保护的贡献（目标 1）。这些实验将推动我们 了解肺部细菌介导的免疫功能障碍的细胞靶标。肺 环境特别容易受到炎症和细菌后果的损害 IL-10刺激亚致死性Spn感染对肺免疫病理学的影响尚不清楚。在第二个目标中 这个提议，我首先确定NK细胞IL-10在Spn期间对肺功能和病理的影响 感染。 IL-10 对细菌清除和肺部炎症的独立影响很难区分。 为了解决这个问题，我将在没有细菌感染的情况下通过滴注细菌来激活 NK 细胞 IL-10 蛋白质直接进入肺部。我们对 Lm 的研究发现，单一毒力蛋白 p60 足以 激活 NK 细胞 IL-10，初步数据显示 p60 滴注可刺激 NK 细胞 IL-10 肺部产生。我们还发现 Spn 表达与 p60 同源的毒力蛋白 在体外激活肺 NK 细胞 IL-10 的产生。我提出的研究使用这些细菌蛋白质来询问 在没有感染的情况下，NK 细胞 IL-10 对肺部炎症的影响以及对肺部炎症的易感性 二次细菌挑战（目标 2）。这些研究将共同​​为如何 呼吸道细菌影响肺稳态。