Wayne State University researchers uncover potential treatment targets for Zika virus-related eye abnormalities

A groundbreaking study provides compelling evidence of cholesterol metabolism involvement in Zika Virus (ZIKV)-related eye abnormalities.

ZIKV infection has been shown to cause neurological disorders, primarily microcephaly - abnormal shrinking of the head circumference. Several clinical studies have linked ZIKV to ocular deformities in infants. These include retinal lesions, microphthalmia, hemorrhagic retinopathy, retinal pigmented epithelium mottling, optic neuritis and hypoplasia of the optic nerve. No specific vaccines or antiviral treatments are available.

"Our study aimed to uncover the molecular mechanisms underlying ZIKV-related eye abnormalities, with a focus on cellular metabolism," said Ashok Kumar, Ph.D., senior author of the study. "By elucidating the roles of key players in cholesterol metabolism, we sought to identify potential targets for therapeutic intervention."

The researchers investigated the functional roles of ATP-binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREBP-2), two critical regulators of cholesterol metabolism, during ocular ZIKV infection. Their cell culture experiments demonstrated that increased ABCG1 activity, mediated via liver X receptors (LXRs), led to reduced ZIKV replication, while inhibition of SREBP-2 reduced viral replication by lowering cholesterol levels.

In vivo studies using mouse models of ZIKV-induced chorioretinal lesions revealed that treatment with an LXR agonist or SREBP-2 inhibitor mitigated ocular abnormalities associated with ZIKV infection. These treatments were accompanied by decreased expression of inflammatory mediators and increased activation of antiviral response genes.

"This study highlights the intricate interplay between cholesterol metabolism and ZIKV infection in the eye," explained Sneha Singh, Ph.D., a postdoctoral fellow in Dr. Kumar's lab.; "Our findings suggest that targeting cholesterol pathway components, such as ABCG1 and SREBP-2, could offer promising therapeutic strategies for mitigating ZIKV-induced ocular complications."