Circadian control of enteric virus infection

肠道病毒感染的昼夜节律控制

基本信息

批准号：
10578706
负责人：
Julie K Pfeiffer
金额：
$ 58.33万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578706
关键词：
ARNTL gene Animals Antiviral Response Binding Biology Cells Circadian Dysregulation Circadian Rhythms Clock protein Complex Coxsackie Viruses Cues Dominant-Negative Mutation Enteral Feedback Gene Expression Gene Proteins Genes Immune Immune response Immunity Immunodeficient Mouse Infection Innate Immune Response Interferon Receptor Interferons Intestines Intraperitoneal Injections Light Link Mammalian Cell Mediating Metabolic Metabolism Molecular Mus Oral Pathologic Periodicity Physiological Processes Physiology Population Process Production Proteins STAT1 gene STAT1 protein Signal Transduction Signaling Protein Time Tissues Transcriptional Regulation Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Wild Type Mouse Work adaptive immune response cell type circadian circadian pacemaker cost enteric virus infection experimental study ileum pathogen promoter response transcription factor vaccination strategy viral RNA

项目摘要

Project Summary/Abstract Circadian rhythms are 24h oscillations in a variety of processes that are entrained by environmental cues including light. Molecularly, this “clock” is driven by key transcription factors and feedback loops that generate rhythmic expression of thousands of mammalian genes in a variety of tissues. Past work has revealed the impact of circadian rhythms on metabolism and immunity. However, the impact of circadian rhythms on infection, particularly enteric virus infection, is understudied. Preliminary experiments using the enteric virus coxsackievirus B3 (CVB3) revealed a profound circadian effect on infection: Mice orally inoculated with CVB3 in the morning had viral titers 10-100 fold lower than mice inoculated in the evening. Inhibition of viral replication in the morning correlated with increased expression of antiviral proteins at this time. Circadian effects on CVB3 infection were lost in mice lacking certain proteins involved in interferon-mediated antiviral responses, suggesting a possible link between circadian transcriptional control and innate immune responses in the intestine. Indeed, expression of an antiviral protein was lost in mice that lack activity of an important clock transcription factor. Thus, CVB3 infection is under circadian control and rhythmic host interferon responses contribute to these effects. However, several questions remain. In this work we will 1) examine mechanisms by which clock transcription factors control expression of innate immune genes, 2) examine the effect of clock transcription factors on infection with CVB3 and other enteric viruses, and 3) identify and evaluate cell types in the intestine that contribute to circadian control of enteric virus infection. Answering these questions will illuminate key, but unanticipated, aspects of intestinal biology that influence enteric virus infection.

项目摘要/摘要在各种过程中，昼夜节律的振荡是由环境提示所带来的包括光。从分子上讲，这个“时钟”是由产生的关键转录因子和反馈回路驱动的各种组织中数千种哺乳动物基因的节奏表达。过去的工作揭示了昼夜节律对代谢和免疫力的影响。但是，昼夜节律对感染，尤其是肠道病毒感染。使用肠道病毒的初步实验 Coxsackievivirus B3（CVB3）揭示了对感染的深刻影响：口服CVB3的小鼠抑制病毒滴度比晚上接种的小鼠低10-100倍。早晨的复制与此时抗病毒蛋白的表达增加有关。昼夜节律在缺乏参与干扰介导的抗病毒的某些蛋白质的小鼠中，对CVB3感染的影响丢失了响应，表明昼夜节律控制与先天免疫反应之间可能存在联系实际上，在缺乏重要活性的小鼠中丧失了抗病毒蛋白的表达时钟转录因子。这就是CVB3感染受昼夜节律控制和节奏的宿主干扰素响应会导致这些影响。但是，还有几个问题。在这项工作中，我们将1）检查时钟转录因子控制先天免疫原子表达的机制，2）检查时钟转录因子对CVB3和其他肠道病毒感染的影响，3）识别和评估肠中的细胞类型，导致昼夜节律对肠道病毒感染的控制。回答这些问题将阐明关键，但意外的是影响病毒的肠生物学方面感染。