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: 10530616
• 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/10530616
• 关键词: Antiviral Response; Binding; Cells; Central Nervous System; 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; Macrophage; Measures; Methods; Modeling; Mus; Pathogenesis; Pathology; Pharmaceutical Preparations; Play; Population; Populations at Risk; Predisposition; Regulation; Research; Research Personnel; Role; Signal Transduction; System; Testing; Time; Training; Transcriptional Regulation; Translating; Vaccines; Viral; Virulence; Virus; Virus Diseases; Work; ZIKV disease; ZIKV infection; Zika Virus; career; experience; experimental study; genome-wide; genome-wide analysis; in vivo; insight; 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.

项目摘要/摘要： 转录因子 (TF) 的干扰素调节因子 (IRF) 家族是抗病毒的中央调节因子 回应。它们将来自病原体识别受体的信号翻译成复杂的转录信号 对于病毒控制至关重要的反应。小鼠 IRF TF 的靶向基因删除增加 对病毒的易感性，病毒反过来又进化出了使 IRF 信号失活的机制，从而导致 毒力增加。尽管IRF很重要，但我们仍然不明白IRF如何协调控制 转录以保护我们免受病毒侵害。 IRF TF 在其 DNA 结合域中具有结构同源性，并且 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 该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 DENV 的原因，以及 不是 ZIKV，它似乎可以刺激 IRF-1 和 IFNγ 反应。其他研究将测试是否缺乏 IFNγ 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 DENV 和 ZIKV 感染期间 IRF 基因激活和转录特征的研究。比较 受感染和未受感染的邻近细胞的反应将识别病毒对宿主细胞信号传导的破坏。 此外，比较 DENV 和 ZIKV 感染细胞的反应将确定病毒特异性激活 IRF 依赖性响应。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控制 IRF 的基本原理 相互之间以及其他 TF 合作建立功能增强子并控制基因表达。 该提案将共同确定 IRF 病毒反应调节的基本原则，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并推进治疗 这些目前无法治疗的感染。

项目成果

Conformational flexibility in neutralization of SARS-CoV-2 by naturally elicited anti-SARS-CoV-2 antibodies.

• DOI: 10.1038/s42003-022-03739-5
• 发表时间: 2022-08-05
• 期刊: Communications biology
• 影响因子: 5.9

Validating Tools to Detect and Inactivate Monkeypox Virus in Human Milk.

验证检测和灭活人乳中猴痘病毒的工具。

• DOI: 10.1089/bfm.2023.0175
• 发表时间: 2023
• 期刊: Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine
• 作者: Clark,AlexE;Furst,Annalee;Sejane,Kristija;Stellwagen,Lisa;Proost,Marissa;Pride,David;Smith,DaveyM;Carlin,AaronF;Bode,Lars
• 通讯作者: Bode,Lars

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing.

• DOI: 10.3390/jof7050366
• 发表时间: 2021-05-07
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Carlin AF;Beyhan S;Peña JF;Stajich JE;Viriyakosol S;Fierer J;Kirkland TN
• 通讯作者: Kirkland TN

Identification of global inhibitors of cellular glycosylation.

• DOI: 10.1038/s41467-023-36598-7
• 发表时间: 2023-02-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sorensen, Daniel Madriz;Bull, Christian;Madsen, Thomas D.;Lira-Navarrete, Erandi;Clausen, Thomas Mandel;Clark, Alex E.;Garretson, Aaron F.;Karlsson, Richard;Pijnenborg, Johan F. A.;Yin, Xin;Miller, Rebecca L.;Chanda, Sumit K.;Boltje, Thomas J.;Schjoldager, Katrine T.;Vakhrushev, Sergey Y.;Halim, Adnan;Esko, Jeffrey D.;Carlin, Aaron F.;Hurtado-Guerrero, Ramon;Weigert, Roberto;Clausen, Henrik;Narimatsu, Yoshiki
• 通讯作者: Narimatsu, Yoshiki

Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern.

结构选择的 RBM 免疫原引发多克隆记忆反应，中和相关的 SARS-CoV-2 变体。

• DOI: 10.1371/journal.ppat.1010686
• 发表时间: 2022-07
• 期刊: PLoS pathogens
• 影响因子: 6.7