AHR is a Zika virus host factor and a candidate target for antiviral therapy
Giovannoni F, Bosch I, Polonio CM, Torti MF, Wheeler MA, Li Z, Romorini L, Rodriguez Varela MS, Rothhammer V, Barroso A, Tjon EC, Sanmarco LM, Takenaka MC, Modaresi SMS, Gutierrez-Vazquez C, Zanluqui NG, Dos Santos NB, Munhoz CD, Wang Z, Damonte EB, Sherr D, Gehrke L, Schatzmann Peron JP, Garcia CC, Quintana FJ (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 23
Pages Range: 939-951
Journal Issue: 8
DOI: 10.1038/s41593-020-0664-0
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.
Authors with CRIS profile
Involved external institutions
Harvard University
United States (USA) (US)
University of São Paulo / Universidade de São Paulo (USP)
Brazil (BR)
Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)
Argentina (AR)
Massachusetts Institute of Technology (MIT)
United States (USA) (US)
Universidad de Buenos Aires (UBA) / University of Buenos Aires
Argentina (AR)
Boston University
United States (USA) (US)
United States (USA) (US)
University of São Paulo / Universidade de São Paulo (USP)
Brazil (BR)
Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI)
Argentina (AR)
Massachusetts Institute of Technology (MIT)
United States (USA) (US)
Universidad de Buenos Aires (UBA) / University of Buenos Aires
Argentina (AR)
Boston University
United States (USA) (US)
How to cite
APA:
Giovannoni, F., Bosch, I., Polonio, C.M., Torti, M.F., Wheeler, M.A., Li, Z.,... Quintana, F.J. (2020). AHR is a Zika virus host factor and a candidate target for antiviral therapy. Nature Neuroscience, 23(8), 939-951. https://doi.org/10.1038/s41593-020-0664-0
MLA:
Giovannoni, Federico, et al. "AHR is a Zika virus host factor and a candidate target for antiviral therapy." Nature Neuroscience 23.8 (2020): 939-951.
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