Zika Virus Infection Triggers Interferon-Dependent Downregulation of Prolyl Oligopeptidase Activity in the Neonatal Brain

Flaviviruses pose a persistent threat to global health; notably, Zika virus (ZIKV) became a focal point of international research during the 2015–2016 Brazilian epidemic due to its association with congenital microcephaly. Although distinct viral lineages are associated with varying pathogenic outcomes, the precise molecular mechanisms driving neuroimmune responses in the developing brain remain poorly defined. Here, we investigated whether neonatal ZIKV infection modulates the activity of the serine protease prolyl oligopeptidase (POP), an enzyme implicated in neuroinflammatory and neuroplasticity regulation. The interplay between POP activity and immune response was also investigated comparing two distinct ZIKV lineages. Newborn mice were infected at postnatal day 0 with either the Brazilian (ZIKV ^BR ) or African (ZIKV ^AF ) strain. We then assessed POP activity, neuroinflammatory markers, interferon signaling and neurotrophic responses at postnatal days 3 (P3) and 7 (P7). At P3, both strains triggered robust innate immune activation - with ZIKV ^AF eliciting a stronger pro-inflammatory while POP activity remained unaltered. By P7, however, ZIKV ^BR infection drove a sustained inflammatory and interferon signaling response that was accompanied by a significant reduction in POP activity. Administration of exogenous IFN-β, at a dosage and regimen previously shown to prevent microcephaly, recapitulated the virus-induced reduction in POP activity. This indicates that type I interferon signaling directly drives this modulation. Together, these findings reveal a novel neuroimmune axis where prolonged, ZIKV-induced Type I interferon signaling suppresses POP activity, highlighting a mechanism by which sustained antiviral responses may alter neurodevelopmental trajectories.