In Silico Designed Axl Receptor Blocking Drug Candidates Against Zika Virus Infection.
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ABSTRACT:
SUBMITTER: Sarukhanyan E
PROVIDER: S-EPMC6044927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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2017-07-06 | GSE89334 | GEO
Project description: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.We intend to characterize ZIKV tropism for human endothelial cells (ECs) and provide potential targets for intervention.We conducted immunostaining, plaque assay, and quantitative reverse transcription-polymerase chain reaction 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 and human ECs derived from aortic and coronary artery, as well as the saphenous vein. Infected ECs released infectious progeny virus. Compared with 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 tyrosine-protein kinase receptor UFO (AXL) receptor tyrosine kinase. Gain- and loss-of-function studies further revealed that AXL is required for ZIKV entry at a postbinding step. Finally, small-molecule inhibitors of the AXL kinase significantly reduced ZIKA infection of ECs.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.
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Project description:Recently, Zika virus (ZIKV) outbreak has been associated with a sharp increase in cases of Guillain-Barré syndrome and severe fetal abnormalities. However, the mechanism underlying the interaction of ZIKV with host cells is not yet clear. Axl, a receptor tyrosine kinase, is postulated as a receptor for ZIKV entry; however, its in vivo role during ZIKV infection and its impact on the outcome of the disease have not been fully characterized and evaluated. Moreover, there are contradictory results on its involvement in ZIKV infection. Here we utilized Axl-deficient mice (Axl-/-) and their littermates (Axl+/-) to study the in vivo role of Axl in ZIKV infection. Our results showed that both Axl+/- and Axl-/- suckling mice supported the replication of ZIKV and presented clinical manifestations. No significant difference has been found between Axl-deficient mice and their littermates in terms of the survival rate, clinical manifestations, viral load, ZIKV distribution and histopathological changes in major organs. These results therefore indicate that Axl is not an indispensable factor for ZIKV infection in mice.
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