AHR is a Zika virus host factor and a candidate target for antiviral therapy.

Nature Neuroscience
Federico GiovannoniFrancisco J Quintana

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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Citations

Dec 3, 2020·Cell Research·Federico Giovannoni, Francisco J Quintana
Dec 15, 2020·Frontiers in Immunology·Miguel A VegaÁngel L Corbí
Feb 15, 2021·European Journal of Medicinal Chemistry·Zdeněk DvořákSridhar Mani
Jan 8, 2021·Cellular & Molecular Immunology·Andreia BarrosoFrancisco J Quintana
Dec 3, 2020·International Journal of Molecular Sciences·Indrek TeinoToivo Maimets
Feb 20, 2021·Current Opinion in Immunology·Andreia BarrosoFrancisco J Quintana
Mar 23, 2021·Frontiers in Immunology·Maria Florencia TortiCybele Carina García
Apr 3, 2021·Frontiers in Immunology·Lilian Gomes de OliveiraJean Pierre Schatzmann Peron
Apr 4, 2021·Veterinary Sciences·Sabari Nath Neerukonda
Apr 4, 2021·International Journal of Molecular Sciences·Adele BoccutoIlaria Vicenti
Apr 9, 2021·Pharmacology & Therapeutics·Marta Marszalek-GrabskaWaldemar A Turski
Jul 3, 2021·International Journal of Molecular Sciences·Yujie Yang, William K Chan
Jul 21, 2021·Molecular Biology Reports·Constanza A RussoCybele C García
Aug 6, 2021·PLoS Neglected Tropical Diseases·Igor Salerno FilgueirasZilton Farias Meira de Vasconcelos
Aug 28, 2021·Nature Communications·Federico GiovannoniFrancisco J Quintana

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Methods Mentioned

BETA
RNA-seq
Flow
ChIP
immunoprecipitation
PCR
flow cytometry
transfections
Transfection
Assay
Enzymatic Shearing

Software Mentioned

NIS
Mulan
QIAGEN
Image J
QIAGEN FlexiTube GeneSolution
Elements Advanced Research
Ingenuity Pathway Analysis ( IPA )
RT 2 profiler
perl scripts
R

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