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

项目总结-通过IFNλ刺激的基因表达对肠道病毒感染的天然免疫 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，同时维持细菌微生物组的屏障功能和耐受性。为了保持这种平衡， 已经进化出对粘膜表面具有特异性的免疫机制。干扰素λ（IFNλ）刺激 肠上皮细胞（IEC）的抗病毒反应，是肠道免疫的关键组成部分， 诺如病毒（MNV）和轮状病毒（MRV）感染的小鼠模型;这种对IFNλ的需求控制了这些病毒的感染。 肠道病毒感染使其区别于其它类型的干扰素。此外，细菌微生物组 以IFNλ受体（IFNLR）依赖的方式促进MNV感染，这表明微生物组 改变IFNλ刺激的抗病毒反应。这项建议旨在缩小我们在理解上的差距 关于IFNλ特有的转录程序，细菌微生物组对这些转录程序的影响， 转录程序和病毒控制所需的特异性干扰素刺激基因（ISG）。具体 目的1将全面描述IEC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将使用新型肠巨噬细胞和IEC共同 培养系统，以确定IFNλ刺激MNV的细胞外源性清除的机制。具体目标 3将确定肠道微生物组在调节IFNλ刺激的抗病毒应答中的作用。 这项工作的长期目标是发现IFN生物学的新方面及其在细胞内的调节。 这将有助于抗病毒药物和免疫疗法的合理发展。

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.