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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.

项目总结/文摘