Zika virus: unraveling the complex interplay between viral pathogenesis and host immune defenses.

Zika virus (ZIKV) is a Flavivirus that has spread globally since its initial reporting. Transmitted to humans via multiple mosquito species, its typical symptoms (e.g., Guillain-Barre syndrome [GBS] and neonatal microcephaly) pose severe public health challenges. Based on existing research, the pathogenic characteristics of ZIKV are largely shaped by host molecular pathways, endowing the virus with an enhanced ability toward specific host cell types. On the other hand, ZIKV achieves intracellular survival and increased pathogenicity by evading the human immune system. Host innate immune responses (autophagy, apoptosis, RNAi, interferon signaling) exert dual effects in ZIKV infection-mediating viral clearance in somatic cells for effective virus control, while aberrant activation or viral evasion of these responses in neural progenitor cells and placental trophoblasts triggers immunopathology, which is the core mechanism of ZIKV neuroinvasion and congenital microcephaly. However, no systematic summary of its precise invasion and defense mechanisms currently exists. This review outlines mechanistic insights into the pathophysiology of ZIKV infection and the strategic mechanisms by which ZIKV evades the host immune system through pathways including autophagy, apoptosis, RNA interference (RNAi), and cell cycle control. We also highlight key limitations in current research, including reliance on in vitro cell lines and animal models that may not fully recapitulate human infection, as well as unresolved mechanistic details of viral-host protein interactions. This work aims to integrate existing knowledge on ZIKV-host crosstalk, providing a framework for future investigations and a basis for developing targeted intervention strategies. Importance. Research on ZIKV is critical due to its global public health impact, particularly its link to severe birth defects like microcephaly and neurological complications. Understanding ZIKV transmission, pathogenesis, and interactions with human hosts provides a scientific basis for the development of potential preventive strategies, diagnostic tools, and vaccine candidates. These studies also illuminate how viruses adapt to novel environments, thereby facilitating preparedness for future outbreaks. Additionally, ZIKV research strengthens global surveillance systems and fosters collaboration across disciplines, benefiting responses to related mosquito-borne diseases. By addressing ZIKV’s unique challenges, this research may help mitigate immediate public health threats posed by ZIKV and provide insights for advancing broader virological knowledge, ultimately protecting vulnerable populations and enhancing long-term health security. The core argument of this review posits that ZIKV engages in a dynamic interplay with the host innate and adaptive immune systems by regulating key pathways such as autophagy, apoptosis, RNAi and cell cycle. The disruption of this equilibrium constitutes the central mechanism underlying pathological features including neurological damage and vertical transmission. This study aims to systematically elucidate the molecular basis of this interaction, thereby providing verifiable theoretical targets for targeted intervention strategies.