Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages.
Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages.
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DOI：
10.1073/pnas.1807690115
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发表时间：
2018-09-25
影响因子：
11.1
通讯作者：
Glass CK
中科院分区：
文献类型：
--
作者：
Carlin AF;Vizcarra EA;Branche E;Viramontes KM;Suarez-Amaran L;Ley K;Heinz S;Benner C;Shresta S;Glass CK
对宿主-病原体相互作用的全基因组研究的解释常常被对感染和未感染细胞的混合群体的分析所掩盖。因此，我们开发了一种系统，通过该系统，我们同时表征和比较病毒感染细胞和邻近未感染细胞的纯种群中全基因组转录和表观遗传变化，以识别病毒调节的宿主反应。利用患者来源的未经修饰的寨卡病毒(ZIKV)感染原代人巨噬细胞，我们揭示了ZIKV通过多种机制抑制宿主转录。ZIKV感染导致I型干扰素反应的靶向抑制，以及通过降低RNA聚合酶II蛋白水平和DNA占有率而引起的普遍抑制。同时评估感染和未感染细胞的转录和表观遗传特征，为鉴定显性前病毒或抗病毒机制的一致进化提供了一种强有力的方法。全基因组范围内对宿主-病原体相互作用的研究往往受限于对感染和未感染细胞的混合群体的分析，这降低了敏感性和准确性。为了克服这些障碍并确定寨卡病毒(ZIKV)操纵宿主反应的关键机制，我们开发了一种系统，能够同时表征感染ZIKV和邻近未感染的原代人类巨噬细胞的全基因组转录和表观遗传变化。我们证明，感染ZIKV的巨噬细胞的转录反应与未感染的邻居完全不同，将细胞群体作为一个整体进行研究会产生误导性的结果。值得注意的是，未感染的巨噬细胞群体在与I型干扰素信号相关的基因表达方面表现出最迅速和最广泛的变化。相反，受感染的巨噬细胞表现出延迟和减弱的转录反应，其特点是在晚期时间点优先表达IFNB1。对感染的巨噬细胞的生化和基因组研究表明，ZIKV感染导致由于STAT2的降解而导致的I型干扰素反应的靶向缺陷，并降低了RNA聚合酶II的蛋白质水平和DNA占有率，特别是在巨噬细胞识别所需的基因上。同时评估感染和未感染的巨噬细胞的转录和表观遗传学特征，从而揭示了决定ZIKV暴露结果的主导前病毒或抗病毒机制的一致进化。
Interpretation of genome-wide investigations of host–pathogen interactions are often obscured by analyses of mixed populations of infected and uninfected cells. Thus, we developed a system whereby we simultaneously characterize and compare genome-wide transcriptional and epigenetic changes in pure populations of virally infected and neighboring uninfected cells to identify viral-regulated host responses. Using patient-derived unmodified Zika viruses (ZIKV) infecting primary human macrophages, we reveal that ZIKV suppresses host transcription by multiple mechanisms. ZIKV infection causes both targeted suppression of type I interferon responses and general suppression by reducing RNA polymerase II protein levels and DNA occupancy. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected cells provides a powerful method for identifying coincident evolution of dominant proviral or antiviral mechanisms. Genome-wide investigations of host–pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results. Notably, the uninfected population of macrophages exhibits the most rapid and extensive changes in gene expression, related to type I IFN signaling. In contrast, infected macrophages exhibit a delayed and attenuated transcriptional response distinguished by preferential expression of IFNB1 at late time points. Biochemical and genomic studies of infected macrophages indicate that ZIKV infection causes both a targeted defect in the type I IFN response due to degradation of STAT2 and reduces RNA polymerase II protein levels and DNA occupancy, particularly at genes required for macrophage identity. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected macrophages thereby reveals the coincident evolution of dominant proviral or antiviral mechanisms, respectively, that determine the outcome of ZIKV exposure.
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DOI：
10.3390/v9100309
发表时间：
2017-10-21
期刊：
Viruses
影响因子：
--
作者：
Harwig A;Landick R;Berkhout B
通讯作者：
Berkhout B
影响因子：
30.5
作者：
Dejnirattisai W;Supasa P;Wongwiwat W;Rouvinski A;Barba-Spaeth G;Duangchinda T;Sakuntabhai A;Cao-Lormeau VM;Malasit P;Rey FA;Mongkolsapaya J;Screaton GR
通讯作者：
Screaton GR
病毒逃避干扰素的十种策略。
影响因子：
30.3
作者：
García-Sastre A
通讯作者：
García-Sastre A
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
158.5
作者：
Driggers, R. W.;Ho, C. -Y.;Vapalahti, O.
通讯作者：
Vapalahti, O.