Role of Zika virus (ZIKV) infection in glaucoma pathobiology

PROJECT SUMMARY The overall goal of this project is to investigate the role of Zika virus (ZIKV) in glaucoma pathobiology. ZIKV is an emerging viral pathogen that causes microcephaly and leads to severe ocular complications in newborns born to ZIKV infected mothers. Although the ocular manifestations of ZIKV are primarily reported to affect the

posterior segment of the eye resulting in chorioretinal atrophy, withering of the retina and choroid, and optic nerve abnormalities, several clinical case reports showed the involvement of the anterior segment resulting in glaucoma. Studies from our laboratory, as well as those of others, have shown that ZIKV can cause

glaucomatous pathology including an increase in intraocular pressure (IOP), retinal ganglion cell (RGC) loss, and optic nerve damage. The offspring of ZIKV infected dams have shown increased IOP and RGC loss and the presence of anti-flavivirus-antibody in these mice correlates with significantly enhanced glaucoma

pathology due to antibody-dependent enhancement. Until the recent ZIKV epidemics, glaucoma has been primarily considered as a genetic and age-related disease and has not been reported among infants exposed to infection during gestation. Several studies have now reported that ZIKV can cause congenital glaucoma in

infants born from mothers who were infected during pregnancy. Considering the fact that there is an endemic transmission of ZIKV in >84 countries, it is imperative to investigate the link between ZIKV and glaucoma to develop new prognostic and therapeutic tools to combat this global health threat. Our laboratory has developed

several in vitro and in vivo models to study the pathobiology of ocular ZIKV infections. In our recent study, we reported that ZIKV can infect and replicate in human primary Trabecular Meshwork cells (HTMC). More recently, we performed RNAseq analysis and discovered that ZIKV infection of HTMC leads to transcriptomic

alteration and dysregulation of several pathways including those that modulate ER stress response, autophagy, hypoxia, and ECM organization. Furthermore, ZIKV-infected mice exhibited increased IOP, ER stress, and autophagy in the anterior segment of the eye. ZIKV infection also caused RGC death and loss of

RGC and optic nerve damage leading to disruption of anterograde axonal transport. Based on these novel findings, we hypothesize that ZIKV induces ER stress and autophagy resulting in TM death and dysfunction, increased IOP, and the development of glaucoma. Two specific aims are proposed to test this hypothesis. Aim

1 will determine the role of ZIKV induced ER stress in TM dysfunction and the pathobiology of glaucoma using C57BL/6 (WT) and IFNAR1-/- mice/pups and whether the reduction of ER stress alleviates ZIKV induced glaucomatous pathology. Aim 2 will investigate the role of autophagy using HTMC, and mouse models and

evaluate the therapeutic efficacy of an FDA approved drug, hydroxychloroquine (HCQ) in ZIKV induced glaucoma. The anticipated results will establish the role of ZIKV infection in the pathogenesis of glaucoma and elucidate the molecular mechanisms and pathway-mediated therapeutic targets for future treatments.