TY - JOUR
T1 - Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
AU - Carlin, Aaron F.
AU - Vizcarra, Edward A.
AU - Branche, Emilie
AU - Viramontes, Karla M.
AU - Suarez-Amaran, Lester
AU - Ley, Klaus
AU - Heinz, Sven
AU - Benner, Christopher
AU - Shresta, Sujan
AU - Glass, Christopher K.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Dr. Aravinda de Silva (University of North Carolina School of Medicine, Chapel Hill) for providing dengue-immune sera. This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases/NIH Grants R01 DK091183 and PPG DK074868 (to C.K.G.), National Institute of Allergy and Infectious Diseases/NIH Grants R01AI116813, R21NS100477, and R21AI127988 and an Interactive Fund Grant from Kyowa Kirin Pharmaceutical Research (to S.S.), and NIH KL2 Grant 1KL2TR001444 of the Clinical and Translational Science Awards (CTSA) Program and a Career Award for Medical Scientists from the Burroughs Wellcome Fund (to A.F.C.).
Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/9/25
Y1 - 2018/9/25
N2 - 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.
AB - 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.
KW - Genomics
KW - Immune evasion
KW - Macrophage
KW - Transcription
KW - Zika virus
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U2 - 10.1073/pnas.1807690115
DO - 10.1073/pnas.1807690115
M3 - Article
C2 - 30206152
AN - SCOPUS:85054011470
SN - 0027-8424
VL - 115
SP - E9172-E9181
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -