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

IFN刺激基因表达对肠道病毒感染的先天免疫

• 批准号: 9918845
• 负责人: Timothy J. Nice
• 金额: $ 38.5万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918845
• 关键词: Age; Antibiotics; Antiviral Agents; Antiviral Response; Bacteria; Biology; Candidate Disease Gene; Cell Culture Techniques; Cells; Cellular Tropism; Childhood; Coculture Techniques; Development; Diarrhea; Enteral; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Face; Gastroenteritis; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Immune; Immunity; Immunotherapy; In Vitro; Infection; Interferons; Intestines; Knock-out; Knockout Mice; Modeling; Mucous Membrane; Mus; Natural Immunity; Norovirus; Receptor Gene; Recombinant Interferon; Regulation; Regulatory Pathway; Role; Rotavirus; Rotavirus Infections; Signal Transduction; Specificity; Surface; System; Testing; Therapeutic; Viral; Virus; Virus Diseases; Work; antiviral immunity; bacteriome; cell type; cytokine; drug development; global health; in vivo; intestinal epithelium; macrophage; microbiome; microbiome alteration; mouse model; novel; prevent; programs; receptor; response; tool; transcriptome

Project Summary - Innate immunity to enteric virus infection by IFNλ-stimulated-gene expression Antiviral immunity in the intestine and other mucosal surfaces faces a distinct challenge: clearance of viral infection while maintaining barrier function and tolerance of the bacterial microbiome. To maintain this balance, immune mechanisms with specificity to mucosal surfaces have evolved. Interferon lambda (IFNλ) stimulates antiviral responses in intestinal epithelial cells (IECs) and is a critical component of intestinal immunity in mouse models of norovirus (MNV) and rotavirus (MRV) infection; this requirement for IFNλ in control of these enteric virus infections distinguishes it from other interferon types. Additionally, the bacterial microbiome promotes MNV infection in an IFNλ receptor- (IFNLR) dependent manner, suggesting that the microbiome alters the IFNλ-stimulated antiviral response. This proposal aims to close the gap in our understanding regarding transcriptional programs unique to IFNλ, the effect of the bacterial microbiome on those transcriptional programs, and the specific interferon stimulated genes (ISGs) required for viral control. Specific Aim 1 will comprehensively characterize the transcriptional response in IECs and identify the genes necessary for cell-intrinsic control of rotavirus infection. Specific Aim 2 will use novel intestinal macrophage and IEC co- culture system to identify mechanisms by which IFNλ stimulates cell-extrinsic clearance of MNV. Specific Aim 3 will determine the role of the commensal microbiome in regulation of IFNλ-stimulated antiviral responses. The long-term goal of this work is to discover novel aspects of IFN biology and its regulation in the intestine that will aid in rational development of antivirals and immunotherapies.

项目总结-干扰素λ刺激基因表达对肠道病毒感染的先天免疫 肠道和其他粘膜表面的抗病毒免疫面临着一个独特的挑战：清除病毒 感染的同时维持细菌微生物群的屏障功能和耐受性。为了保持这种平衡， 具有粘膜表面特异性的免疫机制已经进化。干扰素λ刺激 肠上皮细胞(IECS)中的抗病毒反应，是肠道免疫的关键组成部分 诺如病毒和轮状病毒感染的小鼠模型；这需要干扰素λ来控制这些 肠道病毒感染使其有别于其他类型的干扰素。此外，细菌微生物群 以干扰素λ受体(IFNLR)依赖的方式促进MNV感染，提示微生物群 改变干扰素λ刺激的抗病毒反应。这项建议旨在弥合我们在理解上的差距。 关于干扰素λ特有的转录程序，细菌微生物组对这些程序的影响 转录程序，以及病毒控制所需的特定干扰素刺激基因(ISGs)。特定的 目标1将全面描述IECS的转录反应，并确定必要的基因 用于轮状病毒感染的细胞内在控制。特异性目标2将使用新的肠道巨噬细胞和IEC联合 培养体系，以确定干扰素λ刺激细胞外清除MNV的机制。特定目标 3将确定共生微生物组在调节干扰素λ刺激的抗病毒反应中的作用。 这项工作的长期目标是发现干扰素生物学的新方面及其在 这将有助于合理开发抗病毒药物和免疫疗法。