CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169.
CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169.
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DOI：
10.1128/msphere.00505-21
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发表时间：
2021-06-30
期刊：
影响因子：
4.8
通讯作者：
Ramos I
中科院分区：
文献类型：
--
作者：
Fenutria R;Maringer K;Potla U;Bernal-Rubio D;Evans MJ;Harris E;Rahman AH;Fernandez-Sesma A;Ramos I
寨卡病毒和登革病毒（ZIKV和DENV）是两种黄病毒，负责重要的媒介传播的新发传染病。虽然在过去的几十年中已经有多种DENV流行病，但直到最近几年，ZIKV引起的记录流行病较少。因此，我们目前对ZIKV的生物学、疾病和人类免疫反应的了解是有限的。在此，我们使用质谱细胞术（CyTOF）来进行ZIKV和DENV在来自离体感染的健康供体的人外周血单核细胞（PBMC）中引发的先天免疫应答的详细表征。我们发现人PBMC的ZIKV和DENV暴露诱导骨髓细胞的整体表型变化，其特征主要在于共刺激分子（CD 86和CD 40）、CD 38和I型干扰素诱导蛋白CD 169（骨髓细胞中吞噬功能和交叉引发潜力的标志物）的上调。我们还发现ZIKV诱导细胞培养物中非经典单核细胞的扩增。在单细胞水平上对三种单核细胞亚型（经典型、中间型和非经典型）的表型的分析鉴定了在ZIKV和DENV感染期间它们的⑶ 86、⑶ 38、CXCL 8和CXCL 10表达的差异。总体而言，使用CyTOF，我们发现用ZIKV和DENV离体感染PBMC再现了在先前描述的群组研究中来自患者的血液中发现的谱的许多方面，这突出了该系统用于研究人类宿主对这些病毒的应答的适用性。寨卡病毒和登革热病毒是对公共卫生有重大影响的新出现的虫媒病毒。这两种病毒都是导致重要疾病的原因，但目前还没有疫苗或特定的治疗方法。免疫细胞在病毒周期以及宿主中引发的先天性和适应性免疫应答中起着关键作用;因此，了解病毒感染诱导的外周血单核细胞（PBMC）变化至关重要。在这项研究中，我们使用PBMC的离体感染模型和CyTOF技术来描绘血液中寨卡病毒和登革病毒诱导的早期先天免疫变化。
Zika and dengue virus (ZIKV and DENV) are two flaviviruses responsible for important vector-borne emerging infectious diseases. While there have been multiple DENV epidemics in the last decades, there have been fewer documented epidemics caused by ZIKV until recent years. Thus, our current knowledge about the biology of ZIKV, the disease, and the immune responses in humans is limited. Here, we used mass cytometry (CyTOF) to perform a detailed characterization of the innate immune responses elicited by ZIKV and DENV in human peripheral blood mononuclear cells (PBMCs) from healthy donors infected ex vivo. We found that ZIKV and DENV exposure of human PBMCs induces global phenotypic changes in myeloid cells, characterized mainly by upregulation of costimulatory molecules (CD86 and CD40), CD38, and the type I interferon-inducible protein CD169, a marker for phagocytic function and cross-priming potential in myeloid cells. We also found that ZIKV induces expansion of nonclassical monocytes in cell culture. The analysis of the phenotype of the three monocyte subtypes (classical, intermediate, and nonclassical) at the single-cell level identified differences in their expression of CD86, CD38, CXCL8, and CXCL10 during ZIKV and DENV infection. Overall, using CyTOF, we found that ex vivo infections of PBMCs with ZIKV and DENV reproduced many aspects of the profile found in blood from patients in previously described cohort studies, which highlights the suitability of this system for the study of the human host responses to these viruses. IMPORTANCE Zika and dengue viruses are emergent arboviruses of great public health impact. Both viruses are responsible for important diseases, yet there is currently no vaccine or specific treatment available. Immune cells play critical roles in the virus cycle as well as in the innate and adaptive immune response elicited in the host; therefore, it is critical to understand the changes induced by virus infection in peripheral blood mononuclear cells (PBMCs). In this study, we used a model of ex vivo infection of PBMCs and CyTOF technology to profile the early innate immune changes induced by Zika virus and dengue virus in blood.