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

项目摘要/摘要： 干扰素调节因子(IRFs)家族转录因子是抗病毒的中枢调节因子 回应。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。IRF转录因子在小鼠体内的靶向性基因缺失增加 对病毒的易感性，进而进化出使IRF信号失活的机制，从而导致 毒力增强。尽管它们很重要，但我们仍然不了解红外线如何协调对 转录以保护我们免受病毒侵袭。IRF转录因子在它们的DNA结合域和 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。这个 这项建议的总体目标是确定抗病毒IRF转录因子如何作用于特定基因和基因组 控制抗病毒反应的广泛范围。特定目标1中的实验将调查为什么DENV，以及 而不是ZIKV，似乎能刺激IRF-1和干扰素γ反应。其他研究将测试是否缺乏干扰素γ 反应可以帮助解释ZIKV的神经病理。在特定目标2中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 被感染和未被感染的邻近细胞的反应将识别宿主细胞信号的病毒颠覆。 此外，比较DENV和ZIKV感染细胞的反应将识别病毒特异性激活 依赖IRF的反应。最后，全基因组信号依赖和谱系决定转铁蛋白的整合 活性增强剂的结合和基因组特征将有助于建立支配红外线受体如何 相互协作和其他转录因子建立功能增强子和控制基因表达。 这项提案将共同确定管理IRF对病毒反应的调控的基本原则，并确定 病毒特异性IRF反应的差异可能解释疾病的发病机制和先进的治疗 这些目前无法治愈的感染。

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.