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AHR is a Zika virus host factor and a candidate target for antiviral therapy
Name
nihms-1668695.pdf
Description
Accepted version
Size
4.21 MB
Format
Adobe PDF
Checksum (MD5)
d5ffe99423806f229cfdf616c4b46f40
Author(s)
Giovannoni, Federico
Bosch, Irene
Polonio, Carolina Manganeli
Torti, María F
Wheeler, Michael A
Li, Zhaorong
Romorini, Leonardo
Rodriguez Varela, María S
Rothhammer, Veit
Barroso, Andreia
Date Issued
2020
Journal
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Citation
Giovannoni, Federico, Bosch, Irene, Polonio, Carolina Manganeli, Torti, María F, Wheeler, Michael A et al. 2020. "AHR is a Zika virus host factor and a candidate target for antiviral therapy." Nature Neuroscience, 23 (8).
Version
Author's final manuscript
Abstract
Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity.
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DOI of Published Version
10.1038/S41593-020-0664-0
