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Updated: Aug 25, 2025
Zika Virus Infectious Cell Culture System and the In Vitro Prophylactic Effect of Interferons
Published on: August 23, 2016
Transcriptional and post-transcriptional mechanisms that regulate the genetic program in Zika virus-infected
Geysson Javier Fernandez1, Julieta M Ramírez-Mejía2, Silvio Urcuqui-Inchima3
1Grupo 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.
Abstract:
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.
Insights
Zika virus (ZIKV) infection in macrophages triggers a complex genetic program, including inflammatory and antiviral responses. This study reveals key transcription factors and RNA molecules regulating ZIKV pathogenesis in these critical immune cells.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Zika virus (ZIKV) infection impacts neural cells, but its effects on macrophages, crucial antigen-presenting cells, are less understood.
- The molecular mechanisms governing macrophage gene expression during acute ZIKV infection require further elucidation.
Purpose of the Study:
- To investigate the genetic and regulatory programs activated in macrophages following ZIKV infection.
- To identify key molecular players, including transcription factors, long non-coding RNAs, and microRNAs, involved in the macrophage response to ZIKV.
Main Methods:
- RNA sequencing (RNA-seq) and microRNA sequencing (miRNA-seq) were employed to analyze gene expression profiles.
- Transcriptional control analysis was performed to identify regulatory transcription factors.
- Analysis of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) was conducted to understand post-transcriptional regulation.
Main Results:
- ZIKV infection induced a regulatory program in macrophages involving 1067 differentially expressed genes.
- An inflammatory response mediated by chemokines and an interferon-independent antiviral response, potentially IL-27-driven, were observed.
- Key transcription factors (NFκB, STAT1, HIF1A, ETV7, PRMD1), lncRNAs (MROCKI, ZC2HC1A-2), and miRNAs (miR-155-5p, miR-146a-5p) were identified as regulators of ZIKV-induced gene expression and immune responses.
- RNA binding proteins involved in ribonucleases, splicing, and RNA modification were also implicated.
Conclusions:
- Macrophage response to ZIKV involves intricate transcriptional and post-transcriptional regulatory networks.
- The identified regulatory elements provide insights into ZIKV pathogenesis and potential therapeutic targets.
- This study offers an unbiased approach to understanding the genetic control mechanisms in ZIKV-infected macrophages.
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