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

项目摘要 - 通过 IFNλ 刺激的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独特的挑战：清除病毒 感染，同时保持细菌微生物组的屏障功能和耐受性。为了维持这种平衡， 对粘膜表面具有特异性的免疫机制已经进化。干扰素 lambda (IFNλ) 刺激 肠上皮细胞（IEC）的抗病毒反应，是肠道免疫的重要组成部分 诺如病毒（MNV）和轮状病毒（MRV）感染的小鼠模型； IFNλ 控制这些的要求 肠道病毒感染使其与其他干扰素类型不同。此外，细菌微生物组 以 IFNλ 受体 (IFNLR) 依赖性方式促进 MNV 感染，表明微生物组 改变 IFNλ 刺激的抗病毒反应。该提案旨在缩小我们理解上的差距 关于 IFNλ 独特的转录程序，细菌微生物组对这些转录程序的影响 转录程序，以及病毒控制所需的特定干扰素刺激基因（ISG）。具体 目标 1 将全面表征 IEC 中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。具体目标 2 将使用新型肠道巨噬细胞和 IEC 联合 培养系统以确定 IFNλ 刺激细胞外 MNV 清除的机制。具体目标 图3将确定共生微生物组在调节IFNλ刺激的抗病毒反应中的作用。 这项工作的长期目标是发现 IFN 生物学及其在细胞中的调控的新方面。 肠道，这将有助于抗病毒药物和免疫疗法的合理开发。

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.