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: 10708150
• 负责人: Timothy J. Nice
• 金额: $ 46.2万
• 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/10708150
• 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; 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; Population; Production; Publishing; Receptor Signaling; Regulation; Research; Research Project Grants; Research Proposals; Role; Rotavirus; Rotavirus Infections; Signal Transduction; Site; Sorting; Source; Stimulus; Testing; Tight Junctions; Tissues; Toll-like receptors; Viral; Viral Genes; Virus; Virus Diseases; Vulnerable Populations; Work; antagonist; antiviral immunity; clinically relevant; comparison group; cytokine; enteric virus infection; experimental study; global health; intestinal barrier; intestinal epithelium; laser capture microdissection; microbiota; neonatal mice; pathogenic virus; pharmacologic; 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.

抽象的 由诺如病毒、轮状病毒等肠道病毒病原体引起的胃肠道疾病 严重的全球健康负担，对弱势群体可能致命。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中最有效的元素之一 回复。因此，干扰素通路是疾病治疗的临床相关靶标，并且是重要的治疗靶点。 继续基础研究的领域。我们和其他人已经证明，最近发现的类型 IFN（III 型 IFN，IFN-λ）促进肠上皮细胞 (IEC) 的先天抗病毒免疫，同时最大限度地减少 伴随 I 型干扰素反应的炎症损伤。我们最近的工作现已确定 受细菌微生物群刺激的稳态 IFN-λ 反应，可在细胞内激发抗病毒基因 病毒暴露前的肠上皮。我们对小鼠轮状病毒感染的研究表明，体内平衡 IFN-λ先发制人地限制了 IEC 的病毒感染。本研究计划的目的是定义细胞 肠道内稳态 IFN-λ 产生的来源（目标 1），其表达的机制基础（目标 2) 及其对肠道病毒性疾病的影响（目标 3）。根据我们之前的工作和初步研究，我们的中心 假设肠道树突状细胞在短暂接触细菌期间会产生稳态 IFN-λ 产品，促进上皮细胞先发制人的抗病毒反应。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 类型在肠道病毒病原体的抗病毒免疫中的基本了解。

项目成果

The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus.

• DOI: 10.1016/j.tim.2017.10.010
• 发表时间: 2018-06
• 期刊: Trends in microbiology
• 影响因子: 15.9
• 作者: Nice TJ;Robinson BA;Van Winkle JA
• 通讯作者: Van Winkle JA

A small RNA is functional in Escherichia fergusonii despite containing a large insertion.

尽管含有大的插入片段，小RNA在弗格森埃希氏菌中仍具有功能。

• DOI: 10.1099/mic.0.001099
• 发表时间: 2021
• 期刊: Microbiology (Reading, England)
• 作者: Wright,AustinP;Dutcher,HAuguste;Butler,Brianna;Nice,TimothyJ;Raghavan,Rahul
• 通讯作者: Raghavan,Rahul