Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity
Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK-cell activity
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寨卡病毒感染优先平衡人外周单核细胞和/或 NK 细胞活性
DOI：
10.1101/225102
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Lum F
中科院分区：
文献类型：
--
作者：
Lum F
寨卡病毒（ZIKV）在人群中重新出现，并在全球范围内引发了前所未有的疫情。在这里，首先通过高密度 RNA 测序在人外周血 CD14+ 单核细胞和单核细胞衍生的巨噬细胞中系统地研究了 ZIKV 感染的转录组学后果。对 ZIKV 基因组的分析表明，该病毒经历了遗传多样性，并且在感染过程中在宿主细胞中发现了差异的 mRNA 丰度。值得注意的是，细胞反应发生了显着变化，单核细胞和自然杀伤 (NK) 细胞之间的串扰是高度识别的途径之一。对 ZIKV 感染者外周血的免疫表型分析进一步证实了急性感染期间 NK 细胞的激活。从健康捐献者中分离出的外周血细胞中的 ZIKV 感染导致产生 γ 干扰素 (IFN-γ) 和 CD107a——NK 细胞功能的两个关键标志物。外周血中 CD14+ 单核细胞的消耗导致这些标记物减少，并减少感染期间 NK 细胞的启动。观察到的免疫蛋白质组变化补充了这一点。从机制上讲，ZIKV 感染优先平衡单核细胞和/或 NK 细胞的活性，这对靶向细胞因子免疫疗法具有影响。重要性 近年来，ZIKV 再次出现，在世界许多地区造成疫情爆发。令人担忧的是，ZIKV 感染与神经系统并发症有关，例如成人的吉兰-巴利综合征 (GBS) 和新生儿的先天性胎儿生长相关异常。宿主外周免疫细胞是受感染雌性伊蚊成功传播后最先与病毒相互作用的细胞之一。然而，人们对这些免疫细胞在感染过程中的作用知之甚少。在这项工作中，通过高密度转录组学研究了单核细胞（ZIKV 感染的已知靶细胞）的免疫反应。分析发现，引发了强烈的免疫反应。重要的是，它还揭示了单核细胞在病毒感染期间启动 NK 细胞活动。感染过程中单核细胞的去除改变了免疫环境，从而减少了 NK 细胞的刺激。这项研究为病毒的病理学提供了宝贵的见解，并为设计新型靶向疗法提供了可能性。
Zika virus (ZIKV) has reemerged in the population and caused unprecedented global outbreaks. Here, the transcriptomic consequences of ZIKV infection were studied systematically first in human peripheral blood CD14+monocytes and monocyte-derived macrophages with high-density RNA sequencing. Analyses of the ZIKV genome revealed that the virus underwent genetic diversification, and differential mRNA abundance was found in host cells during infection. Notably, there was a significant change in the cellular response, with cross talk between monocytes and natural killer (NK) cells as one of the highly identified pathways. Immunophenotyping of peripheral blood from ZIKV-infected patients further confirmed the activation of NK cells during acute infection. ZIKV infection in peripheral blood cells isolated from healthy donors led to the induction of gamma interferon (IFN-γ) and CD107a—two key markers of NK cell function. Depletion of CD14+monocytes from peripheral blood resulted in a reduction of these markers and reduced priming of NK cells during infection. This was complemented by the immunoproteomic changes observed. Mechanistically, ZIKV infection preferentially counterbalances monocyte and/or NK cell activity, with implications for targeted cytokine immunotherapies.IMPORTANCEZIKV reemerged in recent years, causing outbreaks in many parts of the world. Alarmingly, ZIKV infection has been associated with neurological complications such as Guillain-Barré syndrome (GBS) in adults and congenital fetal growth-associated anomalies in newborns. Host peripheral immune cells are one of the first to interact with the virus upon successful transmission from an infected femaleAedesmosquito. However, little is known about the role of these immune cells during infection. In this work, the immune responses of monocytes, known target cells of ZIKV infection, were investigated by high-density transcriptomics. The analysis saw a robust immune response being elicited. Importantly, it also divulged that monocytes prime NK cell activities during virus infection. Removal of monocytes during the infection changed the immune milieu, which in turn reduced NK cell stimulation. This study provides valuable insights into the pathobiology of the virus and allows for the possibility of designing novel targeted therapeutics.