Zika virus exploits autophagy for replication in human trabecular meshwork and autophagic inhibition at autolysomal maturation ameliorates Zika-induced ocular complications.

Zika virus (ZIKV) infection causes severe ocular and neurological pathologies in infants following in-utero exposure. ZIKV is also the lone member of Flavivirus, which is known to cause congenital glaucoma. However, the cellular and molecular basis of congenital ZIKV ocular infection and glaucoma are not well understood. Autophagy has been shown to play dual roles in viral infection and glaucoma pathogenesis. However, how ZIKV interferes with autophagic pathways in the trabecular meshwork (TM) and whether autophagy contributes to ZIKV-induced ocular complications remains elusive. In this study, we investigated the role of autophagic pathways in ZIKV pathogenesis in the anterior segment (AS) of the eye utilizing a primary human trabecular meshwork (HTMC) and a IFNAR1-/- mouse model of ocular ZIKV infection. Our results from this study show that ZIKV permissively infects HTMC, induces a dysregulated immune response, and triggers autophagic activity in TM and mouse AS tissue. Our data suggest that although ZIKV initially activates autophagy in TM, it impairs the overall autophagic flux during the course of infection by modulating the VSP39-HOPS complex and STX17-SNARE complex to avoid autolysosomal maturation. We discovered that ZIKV utilizes late-endosomes/lysosomes for their replication and spread in TM. We further demonstrated that modulation of autophagy at the autolysosomal maturation stage with an FDA-approved drug, hydroxychloroquine, or Bafilomycin A1, inhibits ZIKV replication in TM and ameliorates ZIKV-induced ocular pathology in the mouse eyes.Our study is the first to demonstrate the mechanistic insight by which ZIKV manipulates autophagic activity in TM and ocular milieu, and we suggest that the precise modulation of autophagy could be a potential therapeutic avenue for developing new strategies to treat ZIKV-induced ocular complications.