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Model Systems to Study the Pathogenesis of Zika Virus‐Mediated Eye Disease
Author(s) -
Martinez Laura Elizabeth,
Contreras Deisy,
Jones Melissa Kaye,
Gangalapudi Vineela,
Tang Jie,
Wang Shaomei,
Arumugaswami Vaithilingaraja
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.658.12
Subject(s) - biology , zika virus , induced pluripotent stem cell , immunology , retinal pigment epithelium , virology , microcephaly , retina , virus , embryonic stem cell , genetics , neuroscience , gene
Zika virus (ZIKV) is a teratogenic vector‐borne viral pathogen that causes detrimental congenital eye disease, and other disorders such as microcephaly, intrauterine growth restriction, and sensorineural hearing loss. Eye malformations in newborns to mothers infected with ZIKV during pregnancy, such as macular pigment mottling, loss of foveal reflex, intra‐retinal hemorrhages, chorioretinal atrophy, and blindness have been reported. The disease manifestations of congenital ZIKV eye infection are not well understood. Our overall goal is to understand the mechanisms of ZIKV‐mediated ocular injury. We utilized both cell‐based in vitro and animal model systems to address this goal. We first evaluated the permissiveness of fetal retinal pigment epithelium (RPE) cells to ZIKV PRVABC59 (Asian genotype) infection. The RPE is an epithelial cell monolayer present in between photoreceptor cells and the highly vascularized choroid plexus. We observed that RPEs are highly susceptible to ZIKV infection that lead to reduced cell viability and apoptosis. Transcriptomic analysis of infected cells revealed the activation of inflammatory and VEGF signaling pathways, and dysregulation of factors involved in cell survival (PI3K/Akt signaling). Induced pluripotent stem cell‐derived retinal stem cells (iRSCs) supported ZIKV replication at a lower level compared to that of RPE cells. We then investigated the ZIKV disease pathogenesis using a mouse model. The type‐I interferon receptor knockout ( ifnar1 −/− or A129) mice were infected with ZIKV through subcutaneous route. Infected animals showed high viremia at 3 days post infection (dpi). Affected mice showed weight loss and signs of posterior paraplegia at 7 dpi, and reached 100% mortality. ZIKV did not establish efficient infection in wild‐type SJL mice and the infected mice did not show changes in body weight or mortality. Brain tissues from infected ifnar1 −/− mice had the highest viral load, followed by spleen, thymus, eyes, kidney, and heart. Histopathological analysis showed neuroinflammation characterized by extensive perivascular cuffing with neutrophils and mononuclear cells. Infected eyes showed infiltration of cells in the vitreous space and ganglion cell layer. Immunohistochemistry revealed infiltration of macrophages (CD11) and T‐cells (CD4) in the infected retina. We are currently investigating the molecular mechanisms involved in ZIKV infection of the developing eye using a mouse pregnancy model. In conclusion, we provide evidence that fetal retinal epithelial cells and retinal stem cells are susceptible to ZIKV infection, and the described animal model is useful for studying the Zika virulence factors contributing to congenital eye injury and disease pathogenesis. Support or Funding Information Cedars‐Sinai Medical Center