Circadian control of enteric virus infection

项目总结/摘要 昼夜节律是由环境线索所引起的各种过程中的24小时振荡 包括光。在分子上，这个“时钟”由关键转录因子和反馈环驱动， 成千上万的哺乳动物基因在各种组织中有节奏地表达。过去的研究表明， 昼夜节律对新陈代谢和免疫力的影响。然而，昼夜节律的影响， 感染，特别是肠道病毒感染，研究不足。利用肠道病毒的初步实验 柯萨奇病毒B3（CVB 3）揭示了感染的深刻昼夜效应：口服CVB 3的小鼠 早上接种的小鼠的病毒滴度比晚上接种的小鼠低10-100倍。抑制病毒 早晨的复制与此时抗病毒蛋白的表达增加相关。昼夜 在缺乏某些干扰素介导的抗病毒蛋白质的小鼠中， 反应，表明昼夜转录控制和先天免疫反应之间可能存在联系 在肠道里。事实上，一种抗病毒蛋白的表达在缺乏一种重要的抗病毒蛋白活性的小鼠中丢失。 时钟转录因子因此，CVB 3感染是在昼夜节律控制和节律性宿主干扰素 反应有助于这些效果。然而，仍有几个问题。在这项工作中，我们将1）检查 时钟转录因子控制先天免疫基因表达的机制，2）检查 时钟转录因子对CVB 3和其他肠道病毒感染的影响，以及3）鉴定和 评估肠道中有助于肠道病毒感染的昼夜节律控制的细胞类型。回答 这些问题将阐明影响肠道病毒的肠道生物学的关键但未预料到的方面 感染

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.