Circadian control of enteric virus infection

项目摘要/摘要 昼夜节律是受环境提示影响的各种过程中的24小时振荡 包括光。从分子上讲，这个“时钟”是由关键的转录因子和反馈环路驱动的 数以千计的哺乳动物基因在各种组织中有节奏地表达。过去的工作揭示了 昼夜节律对新陈代谢和免疫的影响。然而，昼夜节律对 感染，特别是肠道病毒感染，研究不足。肠道病毒的初步实验 柯萨奇病毒B3(CVB3)对感染具有深刻的昼夜效应：口服接种CVB3的小鼠 早上接种的病毒滴度比晚上接种的小鼠低10-100倍。对病毒的抑制 早晨的复制与此时抗病毒蛋白的表达增加相关。昼夜节律 缺乏干扰素介导的抗病毒相关蛋白的小鼠对CVB3感染的影响 反应，这表明昼夜转录控制和先天免疫反应之间可能存在联系 在肠子里。事实上，在缺乏重要蛋白活性的小鼠中，一种抗病毒蛋白的表达丢失了。 时钟转录因子。因此，CVB3感染处于昼夜节律控制和有节律的宿主干扰素的控制之下 应对措施促成了这些效果。然而，还有几个问题仍然存在。在这部作品中，我们将1)考察 时钟转录因子控制先天免疫基因表达的机制，2)检查 Clock转录因子在CVB3和其他肠道病毒感染中的作用；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。接听 这些问题将阐明影响肠道病毒的肠道生物学的关键但意想不到的方面。 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.