Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures

The genus Flavivirus contains many mosquito-borne human pathogens of global epidemiological importance such as dengue virus, West Nile virus, and Zika virus, which has recently emerged at epidemic levels. Infections with these viruses result in divergent clinical outcomes ranging from asymptomatic to fatal. Myriad factors influence infection severity including exposure, immune status and pathogen/host genetics. Furthermore, pre-existing infection may skew immune pathways or divert immune resources. We profiled immune cells from dengue virus-infected individuals by multiparameter mass cytometry (CyTOF) to define functional status. Elevations in IFNβ were noted in acute patients across the majority of cell types and were statistically elevated in 31 of 36 cell subsets. We quantified response to in vitro (re)infection with dengue or Zika viruses and detected a striking pattern of upregulation of responses to Zika infection by innate cell types which was not noted in response to dengue virus. Significance was discovered by statistical analysis as well as a neural network-based clustering approach which identified unusual cell subsets overlooked by conventional manual gating. Of public health importance, patient cells showed significant enrichment of innate cell responses to Zika virus indicating an intact and robust anti-Zika response despite the concurrent dengue infection.

黄病毒属（Flavivirus）包含诸多经蚊媒传播、具有全球流行病学重要性的人类病原体，如登革病毒、西尼罗河病毒以及近期引发大规模流行的寨卡病毒。此类病毒感染可引发从无症状到致死的多样化临床结局。影响感染严重程度的因素繁多，涵盖暴露史、免疫状态以及病原体与宿主的遗传学特征。此外，既往感染可能会干扰免疫通路或挤占免疫资源。
本研究采用多参数质谱流式细胞术（CyTOF）对登革病毒感染者的免疫细胞进行功能表征分析，以明确其免疫功能状态。研究观察到，急性感染患者体内多数细胞类型的β干扰素（IFNβ）水平均有所升高，其中36个细胞亚群中有31个的IFNβ升高具有统计学显著性。我们还定量检测了体外（再次）感染登革或寨卡病毒后的细胞应答，发现先天免疫细胞对寨卡病毒感染的应答呈现出显著上调的特征，而该特征在登革病毒感染的细胞应答中未被观测到。
研究通过统计学分析与基于神经网络的聚类分析方法验证了该结果的显著性；该聚类方法还识别出了传统手动门控分析所遗漏的异常细胞亚群。具有公共卫生意义的是，患者的免疫细胞对寨卡病毒的先天应答显著富集，这表明尽管同时合并登革病毒感染，机体仍具备完整且强劲的抗寨卡病毒免疫应答。