Lung Epithelial-Immune Interactions In Respiratory Virus Infection

呼吸道病毒感染中肺上皮-免疫相互作用

• 批准号: 8961316
• 负责人: Prabir Ray
• 金额: $ 45.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8961316
• 关键词: Adult; Age; Air; Antiviral Agents; Aryl Hydrocarbon Receptor; Attention; Bronchiolitis; Bronchoalveolar Lavage Fluid; CD59 Antigen; CXCL10 gene; Cell Communication; Cell Count; Cell Line; Cell physiology; Cells; Chimeric Proteins; Data; Defense Mechanisms; Disease; Down-Regulation; Edema; Elderly; Employee Strikes; Epithelial; Epithelial Cells; Epithelium; Genes; Goals; Growth Factor; Hospitalization; Host Defense; Human; Immune; Immune response; Immune system; Infant; Infection; Inflammatory; Interferon-alpha; Interferons; Intestines; Leukocytes; Life; Liquid substance; Lung; Mediating; Mediator of activation protein; Mucin-2 Staining Method; Mucins; Mucous body substance; Mus; Neonatal; Newborn Infant; Outcome; Pathology; Pathway interactions; Patients; Play; Pneumonia; Predisposition; Prevention; Production; Proteins; Publishing; Recombinants; Recruitment Activity; Research Personnel; Respiratory Syncytial Virus Infections; Respiratory physiology; Respiratory syncytial virus; Role; Signal Transduction; Skin; Source; T-Lymphocyte; Tight Junctions; Viral; Virus; Virus Diseases; Virus Replication; Work; airway obstruction; chemokine; cytokine; defense response; differential expression; human data; human subject; improved; in vivo; interleukin-22; mucosal site; peripheral blood; prevent; protective effect; public health relevance; reconstitution; repaired; research study; respiratory infection virus; respiratory virus; response; small hairpin RNA; transcriptome sequencing

 DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) infection can cause severe bronchiolitis and pneumonia in infants and is the primary cause of hospitalization in newborns and infants. However, RSV is generally well-controlled in otherwise healthy adults. Airway epithelial cells (AECs) constitute the primary target of RSV infection. Epithelial cells pla an important role in antiviral host defense by secreting type I (IFN α/ß) interferons that in tur promote expression of interferon-stimulated genes (ISGs). ISGs play a critical role in inhibiting viral replication. IFN-stimulation also causes the production of chemokines such as CXCL10 from epithelial cells that recruit leukocytes to eliminate the virus. We and others have shown that specific growth factors and cytokines such as KGF and IL-22 have epithelial-protective functions. An important source of these factors is the ɣδ T cell. IL-22 produced by ɣδ T cells affords mucosal barrier function for lung and intestinal epithelial cells. It is believed that the primary function of ɣδ T cells is neonatal protection. Previously published human data and our own mouse data show severe loss of IL-22+ɣδ T cells upon RSV infection in early life. Thus, inadequacy of epithelial and ɣδ T cell function in early life can be expected to cause more severe disease during RSV infection. In preliminary studies, RSV infection of human AECs induced several genes with the highest level of response observed for multiple ISGs, including OASL, as determined by RNA-seq analysis. OASL was recently shown to inhibit RSV replication in epithelial cell lines. Expression of infection-induced mucin gene was inhibited by IL- 22 while decrease in expression of a ZO-1-like tight junction protein was prevented. Upon incubation with rIL- 22 a striking inhibition of viral replication was observed in the human AECs. In mouse studies, RSV infection resulted in a drastic loss of IL-22-producing ɣδ T cells, especially in infant mice. RSV induced a weaker CXCL10 response from AECs of infant mice as compared to that from older mice. Collectively, these observations prompt us to hypothesize that the susceptibility to RSV-induced disease in early life is due to inadequate epithelial cell and innate immune antiviral defense response that impair effective host defense against RSV. To prove our hypothesis, we will: Aim 1. Investigate the role of ɣδ T cells and its mediator IL-22 in protectin from RSV infection. Aim 2. Characterize anti-viral defense mechanisms that are induced in RSV-infected human airway epithelial cells and in vivo in mice in the presence or absence of IL-22. Aim 3. Determine the mechanism by which RSV infection results in reduced numbers of ɣδ T cells and IL-22 production by these cells in infant mice. After completion of the proposed studies, we expect to gain a better understanding of interactions between the innate immune system and airway epithelial cells that protect the host from RSV infection.

 描述（由应用提供）：呼吸道合胞病毒（RSV）感染会导致婴儿严重的细支气管炎和肺炎，是新生儿和婴儿住院的主要原因。但是，在其他健康成年人中，RSV通常可以很好地控制。气道上皮细胞（AEC）构成RSV感染的主要靶标。上皮细胞PLA通过分泌I型（IFNα/ß）干扰素在TUR中促进干扰素刺激的基因（ISGS）的表达，在抗病毒宿主防御中起重要作用。 ISGS在抑制病毒复制方面起关键作用。 IFN刺激还会导致趋化因子的产生，例如来自募集白细胞以消除病毒的上皮细胞的CXCL10。我们和其他人表明，特定的生长因子和细胞因子（例如KGF和IL-22）具有上皮保护功能。这些因素的重要来源是ɣδT细胞。 ɣδT细胞产生的IL-22为肺和肠上皮细胞提供粘膜屏障功能。据认为，ɣδT细胞的主要功能是新生儿保护。先前发表的人类数据和我们自己的小鼠数据表明，早期RSV感染后IL-22+ɣδT细胞的严重损失。这是，在RSV感染期间，上皮和ɣδT细胞功能不足会导致更严重的疾病。在初步研究中，人类AEC的RSV感染诱导了几种基因，其中包括多个ISG（包括OASL）的最高反应水平，如RNA-Seq分析确定。最近显示，OASL抑制上皮细胞系中的RSV复制。 IL-22抑制了感染诱导的粘蛋白基因的表达，而防止ZO-1样紧密连接蛋白的表达降低。在与RIL-22孵育后，在人AEC中观察到了对病毒复制的惊人抑制作用。在小鼠研究中，RSV感染导致IL-22产生ɣδT细胞的急剧丧失，尤其是在婴儿小鼠中。与老鼠相比，RSV诱导婴儿小鼠AEC的CXCL10反应较弱。总的来说，这些观察结果促使我们假设对早期RSV引起的疾病的易感性是由于上皮细胞和先天性不足所致 免疫抗病毒防御反应损害了对RSV有效的宿主防御。为了证明我们的假设，我们将：目标1。研究ɣδT细胞及其介体IL-22在RSV感染中的保护素中的作用。 AIM 2。表征在RSV感染的人气道上皮细胞中引起的抗病毒防御机制，在存在或不存在IL-22的情况下，小鼠的体内诱导了体内。 AIM 3。确定RSV感染导致这些细胞在婴儿小鼠中产生的ɣδT细胞数量减少和IL-22产生的机制。拟议的研究完成后，我们希望可以更好地了解保护宿主免受RSV感染的先天免疫系统与气道上皮细胞之间的相互作用。