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

FEDERICO GIOVANNONI; IRENE BOSCH; CAROLINA MANGANELI POLONIO; MARÍA F. TORTI; MICHAEL WHEELER; ZHAORONG LI; LEONARDO ROMORINI; MARÍA SOLEDAD RODRIGUEZ VARELA; VEIT ROTHHAMMER; ANDREIA BARROSO; EMILY C. TJON; LILIANA 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; CYBELE C. GARCIA; FRANCISCO J. QUINTANA

NATURE NEUROSCIENCE.

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2020

1097-6256

Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including fetal 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 activates the aryl hydrocarbon receptor (AHR). AHR activation by ZIKV limits the production of type I interferons involved in innate anti-viral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia protein (PML), which we found limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains, and also of the related flavivirus, dengue virus. Finally, AHR inhibition with nanoparticle-delivered AHR antagonists and specific-inhibitors developed for human use limited ZIKV replication in vivo and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication, and PML as a driver of anti-ZIKV intrinsic immunity.