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: 9273932
• 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/9273932
• 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; Impairment; Infant; Infection; Inflammatory; Innate Immune System; 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; Pathway interactions; Patients; Play; Pneumonia; Predisposition; Prevention; Production; Proteins; Publishing; Pulmonary Pathology; 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; experimental study; human data; human subject; improved outcome; in vivo; interleukin-22; knock-down; mucosal site; peripheral blood; prevent; protective effect; public health relevance; reconstitution; repaired; respiratory infection virus; respiratory virus; response; small hairpin RNA; transcriptome sequencing; γδ T cells

 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（申请人提供）：呼吸道合胞病毒（RSV）感染可引起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。然而，RSV 在其他方面健康的成年人中通常得到良好控制。气道上皮细胞 (AEC) 是 RSV 感染的主要目标。上皮细胞通过分泌 I 型 (IFN α/ß) 干扰素，从而促进干扰素刺激基因 (ISG) 的表达，从而在抗病毒宿主防御中发挥重要作用。 ISG 在抑制病毒复制方面发挥着关键作用。 IFN 刺激还会导致上皮细胞产生趋化因子，例如 CXCL10，这些趋化因子招募白细胞来消除病毒。我们和其他人已经证明，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。这些因子的一个重要来源是ɣδ T 细胞。 ɣδ T 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，ɣδ T 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显示，生命早期感染 RSV 后，IL-22+ɣδ T 细胞严重损失。因此，生命早期上皮细胞和 ɣδ T 细胞功能不足预计会在 RSV 感染期间导致更严重的疾病。在初步研究中，通过 RNA-seq 分析确定，人类 AEC 的 RSV 感染诱导了多个基因，这些基因对多个 ISG（包括 OASL）具有最高水平的反应。最近显示 OASL 可以抑制上皮细胞系中 RSV 的复制。 IL-22抑制感染诱导的粘蛋白基因的表达，同时防止ZO-1样紧密连接蛋白表达的降低。与rIL-22一起孵育后，在人AEC中观察到病毒复制的显着抑制。在小鼠研究中，RSV 感染导致产生 IL-22 的 ɣδ T 细胞急剧减少，尤其是在幼年小鼠中。与年长小鼠相比，RSV 诱导的幼年小鼠 AEC 的 CXCL10 反应较弱。总的来说，这些观察结果促使我们假设生命早期对 RSV 诱发疾病的易感性是由于上皮细胞不足和先天性所致。 免疫抗病毒防御反应，损害宿主对 RSV 的有效防御。为了证明我们的假设，我们将： 目标 1. 研究 ɣδ T 细胞及其介质 IL-22 在保护素免受 RSV 感染中的作用。目标 2. 表征在存在或不存在 IL-22 的情况下，在 RSV 感染的人气道上皮细胞以及小鼠体内诱导的抗病毒防御机制。目标 3. 确定 RSV 感染导致幼鼠体内 ɣδ T 细胞数量减少以及这些细胞产生 IL-22 减少的机制。完成拟议的研究后，我们希望更好地了解先天免疫系统和保护宿主免受 RSV 感染的气道上皮细胞之间的相互作用。