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.