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

FEDERICO GIOVANNONI; IRENE BOSCH; CAROLINA MANGANELI POLONIO; MARÍA F. TORTI; MICHAEL A. WHEELER; ZHAORONG LI; LEONARDO ROMORINI; MARÍA S. RODRIGUEZ VARELA; VEIT ROTHHAMMER; ANDREIA BARROSO; EMILY C. TJON; LILIANA M. SANMARCO; MAISA C. TAKENAKA; SADEQ MODARESI; CRISTINA GUTIÉRREZ-VÁZQUEZ; NÁGELA GHABDAN ZANLUQUI; NILTON BARRETO DOS SANTOS; CAROLINA DEMARCHI MUNHOZ; ZHONGYAN WANG; ELSA B. DAMONTE; DAVID SHERR; LEE GEHRKE; JEAN PIERRE SCHATZMANN PERON; GARCIA, CYBELE; FRANCISCO QUINTANA

NATURE NEUROSCIENCE.

NATURE PUBLISHING GROUP

Año: 2020

1097-6256

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-widetranscriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKVinfection induces kynurenine production, which activates AHR, limiting the production of type I interferons involved in antiviralimmunity. 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, andalso of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developedfor human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identifiedAHR as a host factor for ZIKV replication, and PML protein as a driver of anti-ZIKV intrinsic immunity.