Inflammation Exacerbates Congenital Zika Virus Infection and Naringenin Provides Protective Effects

Zika virus (ZIKV) infection during pregnancy is a critical driver of Congenital Zika Syndrome (CZS), yet the mechanisms of pathogenesis at the placental barrier remain incompletely understood. This article is a translational, observational, and experimental study combining clinical placental analyses, placental explants cultures and in vivo murine model to investigate the mechanisms involved in ZIKV infection. We evaluate the histopathological analyses to verify presence of inflammation in ZIKV-infected human placentas from newborns with CZS and without CZS (N-CZS), identifying more intense Hofbauer cell hyperplasia, villitis and decidual inflammation in CZS group. Moreover, placental immunohistochemistry analyses identified decreased TLR4 expression in the villi and reduced TNF and IL-10 levels across placental layers of CZS group. Next, we investigated the effects of inflammation on viral replication and explored whether the flavonoid Naringenin (NGN) could modulate this inflammation. Using a placental villous explant model, we verified that inflammation induced by LPS exacerbates viral replication and pathological markers. Notably, treatment with the NGN rescued the inflammatory and virological outcomes. These findings were further validated in a murine model of congenital infection, where NGN administration alleviated microcephaly-related structural alterations in ZIKV-exposed neonates. Our results indicate that placental inflammation is a key provocateur of ZIKV replication and subsequent fetal brain malformation. Furthermore, we identify NGN as a promising bifunctional antiviral and anti-inflammatory candidate for mitigating the developmental impacts of ZIKV infection.