Innate immunity to enteric virus infection by IFN-lambda stimulated-gene expression

IFN-lambda 刺激基因表达对肠道病毒感染的先天免疫

• 批准号: 10583367
• 负责人: Timothy J. Nice
• 金额: $ 45.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-09 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583367
• 关键词: Agonist; Antiviral Response; Area; Bacteria; Bone Marrow; Cell Fraction; Cell Separation; Cells; Chimera organism; Clinical Pathways; Data; Dendritic Cells; Development; Disease; Elements; Enteral; Epithelial Cells; Exposure to; Family; Flagellin; Foundations; Gastrointestinal Diseases; Gene Expression; Genes; Genetic; Immune response; Inflammatory; Interferon Type I; Interferons; Intestines; Knock-out; Leukocytes; Lipopolysaccharides; Modeling; Mus; Natural Immunity; Norovirus; PTPRC gene; Pharmacology; Population; Production; Publishing; Receptor Signaling; Regulation; Research; Research Project Grants; Research Proposals; Role; Rotavirus; Rotavirus Infections; Signal Transduction; Site; Source; Stimulus; Testing; Tight Junctions; Tissues; Toll-like receptors; Viral; Virus; Virus Diseases; Vulnerable Populations; Work; antagonist; antiviral immunity; base; clinically relevant; comparison group; cytokine; enteric virus infection; experimental study; global health; intestinal barrier; intestinal epithelium; laser capture microdissection; microbiota; neonatal mice; pathogenic virus; research study; response; single-cell RNA sequencing

ABSTRACT Gastrointestinal diseases caused by enteric viral pathogens such as norovirus and rotavirus impose a significant global health burden and can be lethal in vulnerable populations. For these and other viral pathogens, interferon (IFN) family cytokines are among the most potent elements of the antiviral immune response. Thus, IFN pathways are clinically relevant targets for treatment of disease, and are an important area for continued foundational research. We and others have shown that the most recently discovered type of IFN (type III IFN, IFN-λ) promotes innate antiviral immunity in intestinal epithelial cells (IECs) while minimizing inflammatory damage that can accompany a type I IFN response. Our most recent work has now identified a homeostatic IFN-λ response, stimulated by bacterial microbiota, that elicits antiviral genes within pockets of intestinal epithelium prior to viral exposure. Our studies of mouse rotavirus infection suggest that homeostatic IFN-λ preemptively limits viral infection of IECs. The objective of this research proposal is to define the cellular source of homeostatic IFN-λ production in the intestine (aim 1), the mechanistic basis for its expression (aim 2), and its impact on enteric viral disease (aim 3). Based on our prior work and preliminary studies, our central hypothesis is that intestinal dendritic cells produce homeostatic IFN-λ during transient exposure to bacterial products, promoting preemptive antiviral responses in epithelial cells. Through the studies of this research project, we will identify the basis of the localized homeostatic IFN-λ response in IECs, thereby advancing our fundamental understanding of this IFN type in the antiviral immunity to enteric viral pathogens.

摘要 由肠道病毒病原体如诺如病毒和轮状病毒引起的胃肠道疾病造成了肠道疾病， 严重的全球健康负担，并可能对弱势群体造成致命影响。对于这些和其他病毒 干扰素（IFN）家族细胞因子是抗病毒免疫的最有效的元素之一。 反应因此，IFN途径是治疗疾病的临床相关靶标，并且是重要的免疫调节剂。 继续进行基础研究的领域。我们和其他人已经证明，最近发现的一种 IFN（III型IFN，IFN-λ）促进肠上皮细胞（IEC）的先天性抗病毒免疫，同时最小化 I型干扰素反应可能伴随炎症损伤。我们最近的工作已经确定了一个 由细菌微生物群刺激稳态IFN-λ反应， 在病毒暴露之前的肠上皮。我们对小鼠轮状病毒感染的研究表明， IFN-λ预先限制IEC的病毒感染。这项研究的目的是定义细胞的 肠内稳态IFN-λ产生的来源（目的1），其表达的机制基础（目的 2），及其对肠道病毒性疾病的影响（目的3）。根据我们以前的工作和初步研究，我们的中心 假设肠树突状细胞在短暂暴露于细菌时产生稳态IFN-λ， 产品，促进上皮细胞的抢先抗病毒反应。通过本研究的研究， 项目中，我们将确定IEC中局部稳态IFN-λ反应的基础，从而推进我们的研究。 对这种IFN类型在对肠道病毒病原体的抗病毒免疫中的基本理解。