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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DOI：
10.1128/mspheredirect.00120-18
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发表时间：
2018-03
期刊：
影响因子：
4.8
通讯作者：
Ng LFP
中科院分区：
文献类型：
--
作者：
Lum FM;Lee D;Chua TK;Tan JJL;Lee CYP;Liu X;Fang Y;Lee B;Yee WX;Rickett NY;Chia PY;Lim V;Leo YS;Matthews DA;Hiscox JA;Ng LFP
近年来，寨卡病毒再次出现，在世界许多地方造成疫情。令人震惊的是，寨卡病毒感染与神经系统并发症有关，如成人格林-巴-罗综合征（GBS）和新生儿先天性胎儿生长相关异常。被感染的雌伊蚊成功传播后，宿主外周免疫细胞是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，单核细胞，已知的靶细胞ZIKV感染，研究了高密度转录组学的免疫反应。分析发现，一种强大的免疫反应被激发出来。重要的是，它还揭示了单核细胞在病毒感染期间激活NK细胞的活性。在感染期间去除单核细胞改变了免疫环境，这反过来又减少了NK细胞的刺激。这项研究为病毒的病理生物学提供了有价值的见解，并允许设计新的靶向治疗方法的可能性。寨卡病毒（ZIKV）再次出现在人群中，并引发了前所未有的全球疫情。本研究首先利用高密度RNA测序技术在人外周血CD14+单核细胞和单核细胞源性巨噬细胞中系统地研究了ZIKV感染的转录组效应。对寨卡病毒基因组的分析显示，寨卡病毒经历了遗传多样化，感染期间宿主细胞中mRNA丰度存在差异。值得注意的是，细胞反应发生了显著变化，单核细胞和自然杀伤（NK）细胞之间的串扰是高度确定的途径之一。zikv感染患者外周血的免疫表型分析进一步证实了急性感染期间NK细胞的活化。从健康供体分离的外周血细胞感染ZIKV导致γ干扰素（IFN-γ）和cd107a -两种NK细胞功能的关键标志物的诱导。在感染期间，外周血中CD14+单核细胞的缺失导致这些标记物的减少和NK细胞的启动减少。观察到的免疫蛋白组学变化补充了这一点。从机制上讲，寨卡病毒感染优先平衡单核细胞和/或NK细胞活性，这意味着靶向细胞因子免疫治疗。近年来，寨卡病毒再次出现，在世界许多地区造成疫情。令人震惊的是，寨卡病毒感染与神经系统并发症有关，如成人格林-巴-罗综合征（GBS）和新生儿先天性胎儿生长相关异常。被感染的雌伊蚊成功传播后，宿主外周免疫细胞是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，单核细胞，已知的靶细胞ZIKV感染，研究了高密度转录组学的免疫反应。分析发现，一种强大的免疫反应被激发出来。重要的是，它还揭示了单核细胞在病毒感染期间激活NK细胞的活性。在感染期间去除单核细胞改变了免疫环境，这反过来又减少了NK细胞的刺激。这项研究为病毒的病理生物学提供了有价值的见解，并允许设计新的靶向治疗方法的可能性。
ZIKV 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 female Aedes mosquito. 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. 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. IMPORTANCE ZIKV 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 female Aedes mosquito. 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.