Host defense against influenza virus in the lungs of neonatal mice

新生小鼠肺部宿主对流感病毒的防御

• 批准号: 7914363
• 负责人: Beth A Garvy
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914363
• 关键词: 4 year old; Address; Adoptive Transfer; Adult; Age-Years; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biological Models; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell physiology; Cessation of life; Child; Data; Development; Elderly; Environment; Epigenetic Process; Epithelial Cells; Equilibrium; Failure; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Hospitalization; Host Defense; Human; Immune; Immune Cell Activation; Immune response; Immune system; Immunohistochemistry; Infant; Infection; Infectious Agent; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Interleukin-10; Interstitial Pneumonia; Kinetics; Knock-out; Life; Lung; Measures; Messenger RNA; Modification; Morbidity - disease rate; Mucosal Immune Responses; Mus; Nature; Neonatal; Outcome; Predisposition; Process; Production; Protein Array Analysis; Recommendation; Regulation; Reporting; Respiratory Tract Infections; Risk; Signal Transduction; Site; Sterility; T cell response; T-Lymphocyte; TGFB1 gene; Th1 Cells; Time; Transgenic Mice; Vaccinated; Vaccination; Virus; Virus Diseases; base; cell motility; chemokine; cytokine; influenza virus vaccine; influenzavirus; interstitial; lung development; mature animal; migration; mortality; neonate; neutralizing antibody; novel vaccines; response; treatment strategy

DESCRIPTION (provided by applicant): Infants are particularly susceptible to respiratory infections which have been attributed to an immature and naive immune system that is characterized by suboptimal antigen presentation and a T helper cell bias toward Th2-type cytokines. However, little is known about how the post-natally developing lungs contribute to susceptibility to pulmonary infection. Immune homeostasis in the lungs is controlled by a number of factors including epithelial cell production of IL-10 and TGFB and expression of CD200/CD200R on epithelial cells and alveolar macrophages, respectively. Our data shows elevated levels of TGFB in the lungs of infant mice over the first 3 weeks of life. Moreover, we have previously reported that IL-10 mRNA is constitutively expressed in neonatal lungs. We speculate that these anti-inflammatory cytokines increase the threshold of activation of immune cells in the lungs resulting dampening of inflammation in neonatal lungs. We found that unlike adults, neonatal mice develop interstitial pneumonia in response to influenza virus infection which corresponds to differential expression of chemokines compared to adult mice. The goal of this project is to determine mechanisms that contribute to the differences in T cell migration that may result in the greater susceptibility to virus in neonatal mice. We will address the following hypothesis: The neonatal lung environment alters T cell responses to infection leading to interstitial pneumonia and a worse outcome than in adults. Two aims are proposed: 1) To determine whether neonatal T cells and/or the neonatal lung environment are responsible for development of interstitial pneumonia in response to influenza virus; and 2) To determine the mechanisms responsible for the migration of T cells into the neonatal interstitial spaces but not alveolar spaces. We have chosen to use influenza virus as a models system since influenza virus infection causes more morbidity and mortality than any other infection preventable by vaccination and hospitalization rates among infants with influenza virus rival those of the elderly. Understanding the underlying mucosal immune response to influenza virus in infants is an important step in formulating new treatment strategies for infants. Infants that die from influenza virus have been shown to develop interstitial pneumonia with little infiltration of T cells into the alveolar space. The goal of this project is to understand the processes in post-natally developing lungs that leads to development of interstitial pneumonia in response to infection. Understanding the nature of the failure of the neonatal immune system to control influenza virus is important for generation of new vaccine and treatment strategies.

描述（由申请人提供）： 婴儿特别容易受到呼吸道感染的影响，该呼吸道感染归因于未成熟和天真的免疫系统，其特征是次优抗原表现和T辅助细胞对Th2型细胞因子的偏置。然而，关于本质后发育的肺如何对肺部感染的敏感性有何敏感性知之甚少。肺中的免疫稳态受到许多因素的控制，包括分别在上皮细胞和肺泡巨噬细胞上的IL-10和TGFB的上皮细胞产生以及CD200/CD200R的表达。我们的数据显示，在生命的前三周，婴儿肺中TGFB的水平升高。此外，我们先前已经报道了IL-10 mRNA在新生儿肺中构成表达。我们推测这些抗炎细胞因子会增加肺中免疫细胞激活的阈值，从而导致新生儿肺部炎症减弱。我们发现，与成年人不同，新生小鼠会因响应流感病毒感染而形成间质肺炎，这与成年小鼠相比对应于趋化因子的差异表达。该项目的目的是确定导致T细胞迁移差异的机制，这可能导致新生儿小鼠病毒的敏感性更大。我们将解决以下假设：新生儿肺部环境改变了T细胞对感染的反应，导致间质性肺炎，结果比成年人更糟。提出了两个目的：1）确定新生儿T细胞和/或新生儿肺环境是否负责响应流感病毒的肺炎发展； 2）确定负责T细胞迁移到新生儿间隙空间而不是肺泡空间的机制。我们选择使用流感病毒作为模型系统，因为流感病毒感染会导致与流感病毒竞争的婴儿相比，可预防的疫苗接种和住院率可预防的任何其他感染都会引起更多的发病率和死亡率。了解婴儿对流感病毒的潜在粘膜免疫反应是制定婴儿新治疗策略的重要一步。已证明死于流感病毒的婴儿会发展出间隙性肺炎，而T细胞几乎没有浸润到肺泡空间中。该项目的目的是了解后期发育后发育的肺部的过程，从而导致肺炎发育，以应对感染。了解新生儿免疫系统无法控制流感病毒的性质，对于生成新的疫苗和治疗策略很重要。

项目成果

Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-γ.

• DOI: 10.4049/jimmunol.1300180
• 发表时间: 2013-08-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Breslow-Deckman JM;Mattingly CM;Birket SE;Hoskins SN;Ho TN;Garvy BA;Feola DJ
• 通讯作者: Feola DJ