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

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 develo...

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Autores principales: Carlin, Aaron F., Vizcarra, Edward A., Branche, Emilie, Viramontes, Karla M., Suarez-Amaran, Lester, Ley, Klaus, Heinz, Sven, Benner, Christopher, Shresta, Sujan, Glass, Christopher K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166801/
https://www.ncbi.nlm.nih.gov/pubmed/30206152
http://dx.doi.org/10.1073/pnas.1807690115
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author Carlin, Aaron F.
Vizcarra, Edward A.
Branche, Emilie
Viramontes, Karla M.
Suarez-Amaran, Lester
Ley, Klaus
Heinz, Sven
Benner, Christopher
Shresta, Sujan
Glass, Christopher K.
author_facet Carlin, Aaron F.
Vizcarra, Edward A.
Branche, Emilie
Viramontes, Karla M.
Suarez-Amaran, Lester
Ley, Klaus
Heinz, Sven
Benner, Christopher
Shresta, Sujan
Glass, Christopher K.
author_sort Carlin, Aaron F.
collection PubMed
description 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.
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spelling pubmed-61668012018-10-02 Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages Carlin, Aaron F. Vizcarra, Edward A. Branche, Emilie Viramontes, Karla M. Suarez-Amaran, Lester Ley, Klaus Heinz, Sven Benner, Christopher Shresta, Sujan Glass, Christopher K. Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2018-09-25 2018-09-11 /pmc/articles/PMC6166801/ /pubmed/30206152 http://dx.doi.org/10.1073/pnas.1807690115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Carlin, Aaron F.
Vizcarra, Edward A.
Branche, Emilie
Viramontes, Karla M.
Suarez-Amaran, Lester
Ley, Klaus
Heinz, Sven
Benner, Christopher
Shresta, Sujan
Glass, Christopher K.
Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title_full Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title_fullStr Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title_full_unstemmed Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title_short Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages
title_sort deconvolution of pro- and antiviral genomic responses in zika virus-infected and bystander macrophages
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166801/
https://www.ncbi.nlm.nih.gov/pubmed/30206152
http://dx.doi.org/10.1073/pnas.1807690115
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