Division of Infectious Diseases and Vaccinology, School of Public Health, University of California Berkeley, Berkeley, CA, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Syst Biol. 2018 Aug 27;14(8):e7862. doi: 10.15252/msb.20177862.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in "intermediate" CD14CD16 monocytes and an activated subpopulation of CD14 monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.
基孔肯雅热病毒（CHIKV）是一种虫媒黄病毒，可在全球范围内引发衰弱性疾病的全球流行。为了深入了解病毒感染所需的宿主细胞基因的功能，我们对 42 例自然感染 CHIKV 的儿童的急性和恢复期样本进行了全血 RNA-seq、外周血单个核细胞（PBMC）的 37 重质谱流式细胞术和血清细胞因子测量。对单细胞事件进行半监督分类和聚类为 57 个经典白细胞表型亚群，揭示了急性感染时单核细胞驱动的反应，“中间”CD14CD16 单核细胞和 CD14 单核细胞的激活亚群扩张最大。急性相 CHIKV 包膜蛋白 E2 表达的增加在单核细胞和树突状细胞中最高。血清细胞因子测量证实了单核细胞趋化因子的显著急性相上调。感染时间点以及恢复期抗 CHIKV 抗体滴度、急性相病毒血症和症状严重程度与独特的转录组特征相关。我们提出了一个多尺度网络，总结了所有观察到的细胞和转录组水平的调节及其与临床结果的相互作用，为人类 CHIKV 感染的生物分子景观提供了独特的全局视图。
