Caffeic acid inhibits replication of an Asian lineage Zika virus and attenuates virus-induced inflammatory responses.

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, continues to pose a substantial public health threat, yet no approved antiviral treatment is available. In this study, we investigated the effects of caffeic acid (CA) on ZIKV replication, host-virus interactions, and disease manifestations. CA inhibited ZIKV infection in vitro with ECvalues of 0.60 μM in Vero E6 cells, 0.75 μM in Huh7 cells, and 1.69 μM in A549 cells, while exhibiting low cytotoxicity (CC > 50 μM). Mechanistic experiments revealed that CA curtailed viral RNA accumulation, decreased NS3 protein levels, and lowered the production of infectious progeny virus. In a ZIKV infection model using A129 mice, CA administration decreased viremia, improved survival, minimized weight loss, and attenuated neuropathological damage. Transcriptomic profiling of infected cells, supported by qPCR validation, highlighted that CA attenuates the ZIKV-induced dysregulation of host immune responses, particularly those associated with TNF signaling pathways. Notably, qPCR analysis of inflammatory genes, including TNFAIP3, CXCL8, and CXCL1, confirmed that CA mitigates both virus-induced and TNF-α-driven increases in these inflammatory markers in Huh7 cells. Taken together, these findings suggest that CA not only modulates viral replication but also dampens inflammatory responses linked to ZIKV pathogenesis, providing strong support for its further development as a potential antiviral agent.