Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages

Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9172-E9181. doi: 10.1073/pnas.1807690115. Epub 2018 Sep 11.


Genome-wide investigations of host-pathogen interactions are often limited by analyses of mixed populations of infected and uninfected cells, which lower sensitivity and accuracy. To overcome these obstacles and identify key mechanisms by which Zika virus (ZIKV) manipulates host responses, we developed a system that enables simultaneous characterization of genome-wide transcriptional and epigenetic changes in ZIKV-infected and neighboring uninfected primary human macrophages. We demonstrate that transcriptional responses in ZIKV-infected macrophages differed radically from those in uninfected neighbors and that studying the cell population as a whole produces misleading results. Notably, the uninfected population of macrophages exhibits the most rapid and extensive changes in gene expression, related to type I IFN signaling. In contrast, infected macrophages exhibit a delayed and attenuated transcriptional response distinguished by preferential expression of IFNB1 at late time points. Biochemical and genomic studies of infected macrophages indicate that ZIKV infection causes both a targeted defect in the type I IFN response due to degradation of STAT2 and reduces RNA polymerase II protein levels and DNA occupancy, particularly at genes required for macrophage identity. Simultaneous evaluation of transcriptomic and epigenetic features of infected and uninfected macrophages thereby reveals the coincident evolution of dominant proviral or antiviral mechanisms, respectively, that determine the outcome of ZIKV exposure.

Keywords: Zika virus; genomics; immune evasion; macrophage; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bystander Effect
  • Female
  • Humans
  • Immunity, Innate*
  • Interferon-beta / genetics
  • Interferon-beta / immunology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Proteolysis
  • RNA Polymerase II / genetics
  • RNA Polymerase II / immunology
  • STAT2 Transcription Factor / genetics
  • STAT2 Transcription Factor / immunology
  • Zika Virus / immunology*
  • Zika Virus Infection / immunology*
  • Zika Virus Infection / pathology


  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Interferon-beta
  • RNA Polymerase II