AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus
Rationale: The mosquito-borne Zika virus (ZIKV) is now recognized as a blood-borne pathogen, raising an important question about how the virus gets into human bloodstream. The imminent threat of the ZIKV epidemic to the global blood supply also demands novel therapeutics to stop virus transmission though transfusion.
Objective: We intend to characterize ZIKV tropism for human endothelial cells (ECs) and provide potential targets for intervention.
Methods and Results: We conducted immunostaining, plaque assay, and quantitative RT-PCR of ZIKV RNA to evaluate the possible infection of ECs by ZIKV. Both the African and the South American ZIKV strains readily infect human umbilical vein endothelial cells (HUVECs) and human ECs derived from aortic and coronary artery as well as the saphenous vein. Infected ECs released infectious progeny virus. Compared to the African strains, South American ZIKV isolates replicate faster in ECs and are partially cytopathic, suggesting enhanced virulence of these isolates. Flow cytometric analyses showed that the susceptibility of ECs positively correlated with the cell-surface levels of AXL receptor tyrosine kinase. Gain- and loss-of-function studies further revealed that AXL is required for ZIKV entry at a post-binding step. Lastly, small molecule inhibitors of the AXL kinase significantly reduced ZIKA infection of ECs.
Conclusions: We identified EC as a key cell type for ZIKV infection. These data support the view of hematogenous dissemination of ZIKV and implicate AXL as a new target for antiviral therapy.
- Received August 27, 2016.
- Revision received September 10, 2016.
- Accepted September 19, 2016.