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Abstract
Previously, we reported that Zika virus (ZIKV) causes ocular complications such as chorioretinal atrophy, by infecting cells lining the blood-retinal barrier, including the retinal pigment epithelium (RPE). To understand the molecular basis of ZIKV-induced retinal pathology, we performed a meta-analysis of transcriptome profiles of ZIKV-infected human primary RPE and other cell types infected with either ZIKV or other related flaviviruses (Japanese encephalitis, West Nile, and Dengue). This led to identification of a unique ZIKV infection signature comprising 43 genes (35 upregulated and 8 downregulated). The major biological processes perturbed include SH3/SH2 adaptor activity, lipid and ceramide metabolism, and embryonic organ development. Further, a comparative analysis of some differentially regulated genes (ABCG1, SH2B3, SIX4, and TNFSF13B) revealed that ZIKV induced their expression relatively more than dengue virus did in RPE. Importantly, the pharmacological inhibition of ABCG1, a membrane transporter of cholesterol, resulted in reduced ZIKV infectivity. Interestingly, the ZIKV infection signature revealed the downregulation of ALDH5A1 and CHML, genes implicated in neurological (cognitive impairment, expressive language deficit, and mild ataxia) and ophthalmic (choroideremia) disorders, respectively. Collectively, our study revealed that ZIKV induces differential gene expression in RPE cells, and the identified genes/pathways (e.g., ABCG1) could potentially contribute to ZIKV-associated ocular pathologies.
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1 Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, MI, USA
2 BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Centre, Beth Israel Deaconess Medical Center, Boston, MA, USA; Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3 Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
4 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
5 Department of Neurology, Henry Ford Health System, Detroit, MI, USA
6 Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University, Detroit, MI, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, USA