Mucosal dendritic cell function following enteric virus infection

肠道病毒感染后粘膜树突状细胞的功能

• 批准号: 7924054
• 负责人: Christopher F Cuff
• 金额: $ 21.98万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924054
• 关键词: Address; Adjuvant; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Antiviral Agents; Appearance; CD8B1 gene; Cell physiology; Cells; Cessation of life; Cues; Cytotoxic T-Lymphocytes; Data; Defense Mechanisms; Dendritic Cells; Dendritic cell activation; Differentiation Antigens; Disease; Enteral; Environment; Epithelial Cells; Food; Food Hypersensitivity; Gastroenteritis; Gastrointestinal tract structure; Genes; Genetic Transcription; Goals; Hepatitis; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-10; Interleukin-12; Interleukin-4; Intestinal Mucosa; Intestines; Invaded; Knowledge; Lead; Leukocytes; Macrophage Activation; Mediating; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Multiple Myeloma; Myocarditis; Neuraxis; Oral; Pattern; Pattern recognition receptor; Peanuts - dietary; Phenotype; Population; Process; Production; Reoviridae; Reoviridae Infections; Reovirus; Role; Route; Serum; Signal Transduction; Testing; Tretinoin; United States; Vaccine Adjuvant; Viral Genes; Virion; Virus; Virus Activation; Virus Diseases; Water; commensal microbes; cytokine; foodborne illness; hypersensitivity desensitization; improved; macrophage; microbial; microorganism; mucosal vaccine; pathogen; response; success; vaccine development

DESCRIPTION (provided by applicant): The mucosal immune system must remain tolerant to commensal bacteria and food antigens, yet still maintain the capacity to trigger inflammatory responses to pathogenic microorganisms. The process of initiating inflammatory adaptive immune responses to infection is controlled by multiple populations of dendritic cells (DCs) in the intestinal mucosa. Although it is widely accepted that microbial pathogen associated molecular patterns trigger pattern recognition receptors (PRRs) in DCs, a clear picture as to what factors force dendritic cells into initiating inflammatory responses has not yet emerged. Understanding the processes of how DCs initiate inflammatory responses to enteric virus infection will enhance success in developing mucosal vaccines, which directly addresses the purpose of the RFA entitled Immune Defense Mechanisms at the Mucosa. Enteric reovirus infection induces robust Th1- type immune responses in the intestine that is characterized by production of IFN-?, activation of virus-specific CD8+ cytotoxic T-cells, and appearance of abundant antigen-specific serum antibody of the IgG2a subclass. These observations, along with additional preliminary data support the central hypothesis of this project that the Th1-promoting adjuvant effect of reovirus is due to activation of dendritic cells by cell-free or cell-associated virions, and requires transient viral gene transcription for full activity. Viral gene transcription leads to DC activation through signaling mediated by the intracellular PRRs RIG-1/MDA-5, which induces mucosal DCs to produce Th1 polarizing cytokines such as IL-12. The overall goal of this project is to produce a clearer understanding of how mucosal DCs are stimulated by enteric viruses, thus providing opportunities for advancing the field of mucosal vaccine development. The central hypothesis will be tested with the following Specific Aims: 1) Compare the capacities of replication competent and replication incompetent virus to activate mucosal DCs and macrophages as a result of signaling through intracellular antiviral PRRs, 2) Evaluate the responses of mucosal DCs to cell free reovirus and reovirus-infected IECs, and 3) Demonstrate the capacity of virus-infected mucosal DCs to polarize naive cells to a Th1 phenotype, and determine the role of IL-12 in this response. RELEVANCE: There are up to 2.5 million deaths per year worldwide from food and water-borne diarrheal disease, and it has been estimated that nearly 80% of food-borne illnesses in the United States are due to enteric viruses. Besides gastroenteritis, other diseases caused by enteric viruses include hepatitis, myocarditis, and inflammation of the central nervous system. This project will improve knowledge of how the intestinal immune system initially responds to enteric viruses, and this information will aid in development of vaccines against viruses that invade through the gastrointestinal tract.

描述（由申请人提供）：粘膜免疫系统必须保持对共生细菌和食物抗原的耐受性，但仍保持触发对病原微生物的炎症反应的能力。启动对感染的炎症适应性免疫反应的过程是由肠粘膜中的多个树突状细胞（DC）群体控制的。尽管人们普遍认为微生物病原体相关的分子模式会触发树突状细胞中的模式识别受体（PRR），但关于哪些因素迫使树突状细胞启动炎症反应的清晰图景尚未出现。了解 DC 如何启动对肠道病毒感染的炎症反应的过程将提高粘膜疫苗开发的成功率，这直接解决了题为“粘膜免疫防御机制”的 RFA 的目的。 肠道呼肠孤病毒感染在肠道中诱导强烈的 Th1 型免疫反应，其特征是产生 IFN-α、激活病毒特异性 CD8+ 细胞毒性 T 细胞以及出现丰富的 IgG2a 亚类抗原特异性血清抗体。这些观察结果以及其他初步数据支持了该项目的中心假设，即呼肠孤病毒促进 Th1 的佐剂作用是由于无细胞或细胞相关病毒颗粒激活树突状细胞，并且需要瞬时病毒基因转录才能发挥全部活性。病毒基因转录通过细胞内 PRR RIG-1/MDA-5 介导的信号传导导致 DC 激活，从而诱导粘膜 DC 产生 Th1 极化细胞因子，例如 IL-12。该项目的总体目标是更清楚地了解肠道病毒如何刺激粘膜 DC，从而为推进粘膜疫苗开发领域提供机会。中心假设将通过以下具体目标进行测试：1) 比较复制能力和复制能力不足的病毒通过细胞内抗病毒 PRR 信号传导激活粘膜 DC 和巨噬细胞的能力，2) 评估粘膜 DC 对无细胞呼肠孤病毒和受呼肠孤病毒感染的 IEC 的反应，以及 3) 证明 病毒感染的粘膜 DC 将幼稚细胞极化为 Th1 表型，并确定 IL-12 在这种反应中的作用。 相关性：全世界每年有多达 250 万人死于食物和水源性腹泻病，据估计，美国近 80% 的食源性疾病是由肠道病毒引起的。除胃肠炎外，肠道病毒引起的其他疾病还包括肝炎、心肌炎和中枢神经系统炎症。该项目将提高人们对肠道免疫系统最初如何应对肠道病毒的了解，这些信息将有助于开发针对通过胃肠道入侵的病毒的疫苗。