title: Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes.
abstract: Zika virus (ZIKV) is an important pathogen that causes not only neurologic, but also ocular, abnormalities. Thus, it is imperative that models to study ZIKV pathogenesis in the eye are developed to identify potential targets for interventions. Here, we studied ZIKV interactions with human retinal cells and evaluated ZIKV's pathobiology in mouse eyes. We showed that cells lining the blood-retinal barrier (BRB), the retinal endothelium, and retinal pigment epithelium (RPE) were highly permissive and susceptible to ZIKV-induced cell death. Direct inoculation of ZIKV in eyes of adult C57BL/6 and IFN-stimulated gene 15 (ISG15) KO mice caused chorioretinal atrophy with RPE mottling, a common ocular manifestation of congenital ZIKV infection in humans. This response was associated with induced expression of multiple inflammatory and antiviral (IFNs) response genes in the infected mouse retina. Interestingly, ISG15 KO eyes exhibited severe chorioretinitis, which coincided with increased retinal cell death and higher ZIKV replication. Collectively, our study provides the first evidence to our knowledge that ZIKV causes retinal lesions and infects the cells lining the BRB and that ISG15 plays a role in retinal innate defense against ZIKV infection. Our mouse model can be used to study mechanisms underlying ZIKV-induced chorioretinitis and to gauge ocular antiviral therapies.
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.|Department of Anatomy and Cell Biology, and.
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Guest
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: Mamta
authors.initials: M
authors.lastname: Kanwar
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: Joseph
authors.initials: J
authors.lastname: Boss
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Juzych
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Abrams
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.|Department of Anatomy and Cell Biology, and.
authors.forename: Fu-Shin
authors.initials: FS
authors.lastname: Yu
authors.affiliation: Kresge Eye Institute, Department of Ophthalmology.|Department of Anatomy and Cell Biology, and.|Department of Microbiology, Immunology, and Biochemistry, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001284:Atrophy; D001813:Blood-Retinal Barrier / Q000166:cytology / Q000821:virology*; D016923:Cell Death; D002460:Cell Line; D002825:Chorioretinitis / Q000473:pathology / Q000821:virology*; D002829:Choroid / Q000473:pathology / Q000821:virology*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000821:virology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000473:pathology / Q000821:virology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000473:pathology / Q000821:virology*; D014452:Ubiquitins / Q000235:genetics; D014779:Virus Replication; D000071244:Zika Virus; D000071243:Zika Virus Infection / Q000473:pathology*
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D014452:Ubiquitins