Grupo Inmunovirología, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia; Grupo Biología y Control de Enfermedades Infecciosas, Universidad de Antioquia UdeA, Medellin, Colombia.
CIBIOP group, Department of Applied Sciences and Engineering, Universidad EAFIT, Medellín, Antioquia, Colombia.
Int J Biochem Cell Biol. 2022 Dec;153:106312. doi: 10.1016/j.biocel.2022.106312. Epub 2022 Oct 17.
Besides our understanding of the effects of ZIKA virus (ZIKV) infection on neural progenitors' cells the pathogenesis of this RNA virus also involves antigen-presenting cells, including macrophages. However, the molecular mechanisms that control gene activation and repression associated with the macrophage response to acute ZIKV infection are not fully understood. We approached the issue by RNA-seq and miRNA-seq datasets to understand the genetic program of ZIKV-infected macrophages. Results indicate that macrophage activates a regulatory program, involving 1067 differentially expressed genes. These genetic programs induced an inflammatory response mediated by chemokines as well as an interferon-independent anti-viral response, presumptively activated by IL-27. Additionally, the pathogenetic process involves changes in other signaling pathways such as cellular stress, cell signaling, metabolism, and cell differentiation. Furthermore, transcriptional control analysis revealed regulatory functions of key transcription factors principally, NFκB and STAT1, as well as HIF1A, ETV7, and PRMD1 that are associated with metabolic reprogramming during viral infection. We also noted six long-noncoding RNAs (lncRNAs) that may act in the regulation of gene expression, including MROCKI and ZC2HC1A-2, that are involved in the inflammatory response and expression of the cytokines, respectively. On the other hand, post-transcriptional control by miRNAs, including miR-155-5p and miR-146a-5p, are associated with modulation of genes related to inflammatory and antiviral responses. Relevant to the post-transcriptional control, our data unveiled the role of RNA binding proteins that have diverse functions such as ribonucleases (PNPT1, ZC3H12A, and ZC3HAV1), splicing factors (SSB, RBM11, and RAVER2), and RNA modifiers (PARP10 and PARP14). Overall, the results establish an unbiased approach to discerning the wiring of a regulatory mechanism controlling the genetic program in ZIKV-infected macrophages.
除了我们对寨卡病毒（ZIKV）感染对神经祖细胞的影响的理解之外，这种 RNA 病毒的发病机制还涉及抗原呈递细胞，包括巨噬细胞。然而，控制巨噬细胞对急性 ZIKV 感染反应的基因激活和抑制的分子机制尚未完全阐明。我们通过 RNA-seq 和 miRNA-seq 数据集来研究这个问题，以了解 ZIKV 感染的巨噬细胞的遗传程序。结果表明，巨噬细胞激活了一个调节程序，涉及 1067 个差异表达的基因。这些基因程序诱导了一种炎症反应，由趋化因子介导，以及一种干扰素非依赖的抗病毒反应，可能是由 IL-27 激活的。此外，病原体的过程还涉及其他信号通路的变化，如细胞应激、细胞信号转导、代谢和细胞分化。此外，转录控制分析显示了关键转录因子的调节功能，主要是 NFκB 和 STAT1，以及 HIF1A、ETV7 和 PRMD1，它们与病毒感染期间的代谢重编程有关。我们还注意到六个长非编码 RNA（lncRNA）可能在基因表达的调节中发挥作用，包括 MROCKI 和 ZC2HC1A-2，它们分别参与炎症反应和细胞因子的表达。另一方面，miRNA 的转录后控制，包括 miR-155-5p 和 miR-146a-5p，与与炎症和抗病毒反应相关的基因的调节有关。与转录后控制相关的是，我们的数据揭示了 RNA 结合蛋白的作用，这些蛋白具有多种功能，如核糖核酸酶（PNPT1、ZC3H12A 和 ZC3HAV1）、剪接因子（SSB、RBM11 和 RAVER2）和 RNA 修饰物（PARP10 和 PARP14）。总的来说，这些结果提供了一种无偏的方法来辨别控制 ZIKV 感染的巨噬细胞中遗传程序的调节机制的布线。
