Targeting first trimester trophoblast cell metabolism modulates its susceptibility to Zika virus infection

KAFE, DIEGO; MARQUEZ, AGOSTINA B.; MERECH, FÁTIMA; HAUK, VANESA; PAPARINI, DANIEL; RAMHORST, ROSANNA; PEREZ LEIROS, CLAUDIA; GARCIA, CYBELE; VOTA, DAIANA

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2023

0021-9541

In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale inMicronesia, South Pacific islands, and more recently in the Caribbean and South America. Theseverity of the clinical presentation in neonates from pregnant women infected with ZIKVduring the last outbreak supports the relevance of unraveling the mechanism of infection andviral persistence in the placenta with local viral isolates. Here, we investigated the relevance oftrophoblast metabolic rewiring for viral multiplication and the role of the vasoactive intestinalpeptide (VIP) as an endogenous factor associated with placental restriction to ZIKV infection atearly pregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring in firsttrimester cytotrophoblast-derived cells by increasing glucose utilization as fuel to sustain itsreplication, decreasing long chain polyunsaturated fatty acid uptake, and promoting lipiddroplets accumulation to favor its multiplication. Of note, variations in nutrient availabilitymodulated viral spread in trophoblast cultures. The presence of VIP during trophoblastinfection impaired ZIKV infective particle production and viral replication, restoring cellmigration and metabolism. Moreover, the blockade of endogenous VIP signaling increasedviral particle production and the viral entry receptor AXL expression. These results highlightthe potential role of VIP as an endogenous antiviral factor related to trophoblast cellpermissiveness to ZIKV infection at early pregnancy.