Deconvolution of pro- and anti-viral responses to Dengue virus and Zika Virus infections

对登革热病毒和寨卡病毒感染的亲病毒反应和抗病毒反应的反卷积

• 批准号: 10082422
• 负责人: Aaron F. Carlin
• 金额: $ 20.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082422
• 关键词: Antiviral Agents; Antiviral Response; Binding; Cells; ChIP-seq; Chromatin; Clinical; Clinical Investigator Award; Complex; DNA; DNA Binding Domain; Data; Data Set; Dengue Infection; Dengue Virus; Disease; Enhancers; Epigenetic Process; Family; Family member; Flavivirus; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Human; IRF1 gene; IRF3 gene; Immune response; In Vitro; Individual; Infection; Interferon Activation; Interferon Type II; Interferons; Knockout Mice; Life; Measures; Methods; Modeling; Mus; Neuraxis; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Population; Predisposition; Regulation; Research; Research Personnel; Risk; Role; Signal Transduction; Structure; System; Testing; Time; Training; Transcriptional Regulation; Translating; Vaccines; Viral; Virulence; Virus; Virus Diseases; Work; ZIKV disease; ZIKV infection; Zika Virus; activating transcription factor; career; experience; experimental study; genome-wide; in vivo; insight; macrophage; member; monocyte; mortality; neuropathology; pathogen; prevent; programs; receptor; response; transcription factor; transcriptome sequencing; transcriptomics; viral interferon regulatory factor

Project Summary/Abstract: The interferon-regulatory factor (IRFs) family of transcription factors (TFs) are central regulators of anti-viral responses. They translate signals from pathogen recognition receptors into complex transcriptional responses that are essential for viral control. Targeted genetic deletion of IRF TFs in mice increase susceptibility to viruses, which in turn have evolved mechanism to deactivate IRF signaling leading to increased virulence. Despite their importance, we still do not understand how IRFs coordinate the control of transcription to protect us from viruses. IRF TFs share structural homology in their DNA binding domains and bind highly similar DNA motifs. Yet, they regulate non-redundant antiviral transcriptional programs. The overall objective of this proposal is to determine how anti-viral IRF TFs act on a gene specific and genome wide scale to control anti-viral responses. The experiments in specific aim 1 will investigate why DENV, and not ZIKV, appears to stimulate IRF-1 and IFNγ responses. Additional studies will test if the lack of IFNγ response can help explain ZIKV neuropathology. Studies in specific Aim 2 will identify genome-wide networks of IRF gene activation and transcriptional signatures during DENV and ZIKV infections. Comparisons of responses in infected and uninfected neighboring cells will identify viral subversion of host cell signaling. Additionally, comparing responses in DENV and ZIKV infected cells will identify viral specific activation of IRF-dependent responses. Lastly, integration of genome-wide signal dependent and lineage determining TF binding and genomic features of active enhancers will help establish basic principals governing how IRFs cooperate with each other and other TFs to establish functional enhancers and control gene expression. Together this proposal will identify basic principals governing IRF regulation of viral responses and identify differences in viral specific IRF responses that may explain disease pathogenesis and advance treatments for these currently untreatable infections.

项目概要/摘要： 干扰素调节因子（IRFs）家族的转录因子（TF）是抗病毒药物的中心调节因子。 应答它们将病原体识别受体的信号翻译成复杂的转录 对病毒控制至关重要的反应。小鼠中IRF TF的靶向遗传缺失增加 对病毒的易感性，这反过来又进化出了使IRF信号转导失活的机制， 毒性增强。尽管它们很重要，但我们仍然不了解区域间框架如何协调对 保护我们免受病毒侵害IRF TF在其DNA结合结构域中具有结构同源性， 结合高度相似的DNA基序。然而，它们调节非冗余的抗病毒转录程序。的 本提案的总体目标是确定抗病毒IRF TF如何作用于基因特异性和基因组 大规模控制抗病毒反应。具体目标1中的实验将研究为什么DENV， 而不是ZIKV似乎刺激IRF-1和IFNγ应答。进一步的研究将测试如果缺乏IFNγ 这种反应可以帮助解释ZIKV神经病理学。具体目标2的研究将确定全基因组网络 在DENV和ZIKV感染期间IRF基因激活和转录特征的研究。比较 感染和未感染的邻近细胞中的应答将鉴定宿主细胞信号传导的病毒破坏。 另外，比较DENV和ZIKV感染的细胞中的应答将鉴定DENV和ZIKV感染的细胞的病毒特异性活化。 IRF依赖性反应。最后，整合全基因组信号依赖和谱系决定TF 活性增强子的结合和基因组特征将有助于建立管理IRFs如何 相互之间以及与其他TF合作以建立功能增强子并控制基因表达。 总之，该提案将确定IRF调节病毒反应的基本原则，并确定 病毒特异性IRF反应的差异，可以解释疾病的发病机制和先进的治疗方法， 这些目前无法治愈的感染