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

KAFER, DIEGO; MARQUEZ, AGOSTINA; MERECH, FÁTIMA; HAUK, VANESA; PAPARINI, DANIEL; RAMHORST, ROSANNA; LEIRÓS, CLAUDIA PÉREZ; GARCIA, CYBELE; VOTA, DAIANA

JOURNAL OF CELLULAR PHYSIOLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

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 SouthAmerica. The severity of the clinical presentation in neonates from pregnant womeninfected with ZIKV during the last outbreak supports the relevance of unraveling themechanism of infection and viral persistence in the placenta with local viral isolates.Here, we investigated the relevance of trophoblast metabolic rewiring for viralmultiplication and the role of the vasoactive intestinal peptide (VIP) as anendogenous factor associated with placental restriction to ZIKV infection at earlypregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring infirst trimester cytotrophoblast‐derived cells by increasing glucose utilization as fuelto sustain its replication, decreasing long‐chain polyunsaturated fatty acid uptake,and promoting lipid droplets accumulation to favor its multiplication. Of note,variations in nutrient availability modulated viral spread in trophoblast cultures.The presence of VIP during trophoblast infection impaired ZIKV infective particleproduction and viral replication, restoring cell migration and metabolism. Moreover,the blockade of endogenous VIP signaling increased viral particle production and theviral entry receptor AXL expression. These results highlight the potential role of VIPas an endogenous antiviral factor related to trophoblast cell permissiveness to ZIKVinfection at early pregnancy.