Plasminogen activator inhibitor-1 regulates Zika virus infection

Zika virus (ZIKV) infection can lead to severe congenital outcomes, yet the mechanisms governing its entry into host cells remain understood. ZIKV is a flavivirus known to exploit multiple cellular receptors and cofactors, particularly in neural cells, where infection can result in congenital Zika syndrome (CZS). Here we show that plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor involved in hemostasis, directly interacts with ZIKV particles and critically enhances viral replication in diverse cell types, including human neural progenitor cells and three-dimensional neural organoids. Our findings reveal that PAI-1 may contribute to ZIKV infection through distinct or complementary pathways, underscoring the virus’s versatile entry mechanisms. Inhibition of PAI-1 via tiplaxtinin (TPX) dramatically reduces viral load and impedes infectious particle release, demonstrating a dose-dependent effect that is especially potent in neural models relevant to CZS. These results highlight PAI-1 as an essential mediator of ZIKV pathogenesis and suggest that targeting PAI-1 function could represent a novel therapeutic avenue. Given the risk of future ZIKV outbreaks and the devastating impact of CZS, interventions aimed at PAI-1 may hold promise for reducing the global burden of ZIKV infection.