IL-10 producing neutrophils during respiratory virus infection

呼吸道病毒感染期间产生 IL-10 中性粒细胞

• 批准号: 9110188
• 负责人: Carolina B. Lopez
• 金额: $ 20万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110188
• 关键词: Acute; Address; Antiviral Agents; CSF3 gene; Cells; Child; Chronically Ill; Clinical Management; Data; Elderly; Environment; Future; Goals; Grant; Healed; Health; Homeostasis; Human; Hyperoxia; Immature Granulocyte; Immune; Immunocompromised Host; Immunosuppressive Agents; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Interferon Type I; Interleukin-10; Life; Lung; Lung Inflammation; Maintenance; Mechanical Ventilators; Mediating; Molecular Target; Morbidity - disease rate; Mus; Myeloid Cells; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Play; Population; Process; Pulmonary Inflammation; Recruitment Activity; Regulation; Reporter; Respiratory System; Respiratory Tract Infections; Respiratory syncytial virus; Respiratory tract structure; Risk; Role; Sendai virus; Signal Transduction; Staging; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Vaccination; Viral Respiratory Tract Infection; Virus; Virus Diseases; asthmatic patient; cellular targeting; congenital heart disorder; cytokine; granulocyte; healing; high risk; immunosuppressed; improved; in vivo; influenzavirus; interest; mouse model; neutrophil; novel; novel therapeutics; prevent; respiratory infection virus; respiratory virus; response; targeted treatment

DESCRIPTION (provided by applicant): Infections of the respiratory tract with viruses such as influenza or respiratory syncytial virus are a constant challenge to human health, particularly to children, the elderly, and the immunocompromised. Deregulation of the inflammatory response developed to control and clear the infection leads to life threatening disruption of the respirator tract physiology and loss of integrity of the mucosal barrier, thereby largely contributing to the high degree of morbidity associated with these infections. Understanding the mechanisms that regulate the inflammatory response to infection is essential to identify targets for therapeutic intervention. Our data indicate that neutrophils that are recruited to the lung early upon respiratory viral infections play an essential role in regulating the extent of the inflammatory response. Interestingly, a fraction of these neutrophils produce the regulatory cytokine IL-10, and IL-10 expression by these cells is stimulated by the antiviral cytokines type I interferons produced in the lung during infection. As neutrophils are massively recruited to the lung at the early stages of viral infections, we hypothesize that in response to the antiviral inflammatory environment, a population of neutrophils acquire a regulatory phenotype that significantly contributes to protection from lung damage and associated pathologies. Supporting this hypothesis, mice bearing IL-10 deficient myeloid cells developed a more severe lung inflammation and showed enhanced morbidity. Here, we will use cutting edge technology to characterize IL-10-producing neutrophils present in the lung of mice infected with respiratory syncytial virus (Aim 1), we will determine whether type I IFN priming is required for the neutrophil protective activity (Aim 2), and we will test whether neutrophil-produced IL-10 modulates the inflammatory response to virus infection (Aim 3). Overall, this exploratory R21 grant aims at morphologically and phenotypically characterizing pulmonary IL-10-producing neutrophils present during respiratory viral infections, and to advance our understanding of their function in lung protection. These studies should guide future identification of molecular targets for the harnessing of the neutrophil protective activities in patients.

描述（由申请方提供）：流感或呼吸道合胞病毒等病毒的呼吸道感染是对人类健康的持续挑战，特别是对儿童、老年人和免疫功能低下者。为控制和清除感染而产生的炎症反应的失调导致呼吸道生理学的危及生命的破坏和粘膜屏障完整性的丧失，从而在很大程度上导致与这些感染相关的高度发病率。了解调节感染炎症反应的机制对于确定治疗干预的靶点至关重要。 我们的数据表明，在呼吸道病毒感染早期被招募到肺部的中性粒细胞在调节炎症反应的程度方面起着重要作用。有趣的是，这些中性粒细胞的一部分产生调节细胞因子IL-10，这些细胞的IL-10表达受到感染期间肺中产生的抗病毒细胞因子I型干扰素的刺激。由于中性粒细胞在病毒感染的早期阶段大量募集到肺中，我们假设，在对抗病毒炎症环境的反应中，中性粒细胞群体获得了一种调节表型，该表型显著有助于保护免受肺损伤和相关病理。支持这一假设，携带IL-10缺陷型骨髓细胞的小鼠发展为更严重的肺部炎症，并显示出增加的发病率。在这里，我们将使用尖端技术来表征呼吸道合胞病毒感染的小鼠肺中存在的产生IL-10的中性粒细胞（目的1），我们将确定中性粒细胞保护活性是否需要I型IFN引发（目的2），我们将测试嗜中性粒细胞产生的IL-10是否调节对病毒感染的炎症反应（目的3）。 总的来说，这项探索性的R21资助旨在从形态学和表型上表征呼吸道病毒感染期间存在的肺部产生IL-10的中性粒细胞，并促进我们对它们在肺保护中的功能的理解。这些研究应该指导未来的分子靶点识别，以利用患者的中性粒细胞保护活性。