Breaking barriers and beyond: mechanisms and pathological implications of Zika virus traversal across blood-tissue interfaces

Blood-tissue barriers are specialized interfaces that safeguard organ homeostasis by restricting pathogen dissemination. Zika virus (ZIKV), an emerging flavivirus of global concern, exhibits an exceptional ability to breach multiple barriers—including the blood-brain, blood-placental, blood-testis, and blood-retinal barriers—enabling neuroinvasion, vertical and sexual transmission, and ocular disease. ZIKV employs diverse strategies to cross these barriers: receptor-mediated entry, disruption of tight junctions, and hijacking immune cells or extracellular vesicles as viral carriers. Adaptive mutations further refine tissue tropism and enhance barrier traversal efficiency. Insights from cell culture, organoid, animal, and ex vivo tissue models reveal not only the conserved and tissue-specific mechanisms of barrier penetration but also the downstream pathological consequences in the affected organs. Understanding how ZIKV breaches these interfaces and induces organ-specific pathology deepens our knowledge of host-pathogen interactions and provides a framework for designing barrier-protective and disease-mitigating strategies against ZIKV and other pathogens that breach blood-tissue barriers. • Comprehensive analysis of ZIKV traversal across four key blood-tissue barriers: BBB, BPB, BTB, and BRB. • Summarizes the molecular and cellular mechanisms enabling ZIKV to disrupt tight junctions and barrier integrity. • Adaptive mutations in viral proteins enhance tissue tropism and barrier penetration. • Barrier disruption causes organ-specific damage, including microcephaly, testicular dysfunction, and chorioretinal atrophy. • Provides an integrated framework linking ZIKV barrier breach to organ-specific pathogenesis and prevention strategies.