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

(Image Credit: AdobeStock/anatolir)

In a recent study, a team of researchers from Wayne State University have detailed key insights into the ocular effects of Zika virus infection during pregnancy and offers promising avenues for therapeutic intervention.

The study was published recently in iScience.¹

According to a Wane State University news release, the paper was produced by a team of researchers in the Department of Ophthalmology, Visual and Anatomical Sciences at the university’s School of Medicine. Titled “Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology,” the paper provides compelling evidence of the involvement of cholesterol metabolism in ZIKV-related eye abnormalities.²

The university noted in its news release that while congenital 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.

Moreover, despite the ZIKV infection causing severe neurological and ocular abnormalities in infants, no specific vaccines or antiviral treatments are available. In their research, the team conducted a transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells, revealing significant alterations in the cholesterol pathway.

“Our study aimed to uncover the molecular mechanisms underlying ZIKV-related eye abnormalities, with a focus on cellular metabolism,” Ashok Kumar, PhD, professor of ophthalmology, visual and anatomical sciences, and senior author of the study, said in the news release. “By elucidating the roles of key players in cholesterol metabolism, we sought to identify potential targets for therapeutic intervention.”

According to the news release, 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.²

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.

Sneha Singh, PhD, a postdoctoral fellow in Kumar’s lab, pointed out that the study highlights the intricate interplay between cholesterol metabolism and ZIKV infection in the eye.

“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,” Singh said in the news release.

“The implications of our study extend beyond Zika virus, as the mechanisms uncovered can potentially apply to other enveloped viruses such as West Nile virus, Japanese encephalitis virus and Dengue virus,” Kumar said.

According to the news release, Kumar’s team is utilizing a lipidomics approach to pinpoint lipid molecules possessing both proviral and antiviral properties, with the overarching goal of unearthing novel antiviral therapeutics.

The university noted in its news release the publication of the paper underscores its commitment to advancing scientific knowledge and addressing pressing global health challenges. The interdisciplinary collaboration and innovative methodologies employed in this research exemplify the institution’s dedication to excellence in scientific inquiry.2

Ezemenari M. Obasi, PhD, vice president for research at Wayne State, noted in the news release that the work of Kumar’s team has placed them at the forefront of developing breakthroughs that will play a vital role in therapeutic interventions in eye abnormalities caused by the Zika virus.

“This study is an excellent example of how Wayne State’s research is making discoveries that can impact lives in Detroit and around the world,” Obasi said.

“Our study demonstrates the role of ABCG1 and SREBP-2, the two arms of the cholesterol/lipid homeostasis pathway in regulating the innate antiviral response in RPE during ZIKV infection,” the researchers wrote in the study. “Thus, ABCG1 and SREBP-2 regulated cholesterol homeostasis can be targeted to mount antiviral innate response during ocular ZIKV infection.”

The researchers noted there are some limitations to the study.¹

According to researchers, SREBP-2 is known to regulate the transcription of ABCG1 expression to maintain cholesterol homeostasis and vice-versa. However, their cross-talk during ZIKV infection has not been investigated in the present study. Also, the molecular mechanism of how ABCG1 and SREBP-2 regulate antiviral innate immune response needs further investigation.

“Here, we primarily focused on cholesterol, the role of other lipids produced by the activation of SREBP-2 upon ZIKV infection also needs to be evaluated,” the researchers concluded in the study. “The drugs were administered via intravitreal injections in our infection model; however, the systemic route of injection of the drugs for the treatment of ZIKV-induced retinal lesions would be interesting.”

According to the university’s news release, the team’s research was made possible through funding from the National Institutes of Health’s National Eye Institute (Grants: R21AI135583, R01EY026964, 1R01EY032149-01 and R01 EY027381).²

Reference

1. Sneha Singh, Robert E. Wright III, Shailendra Giri, Vaithilingaraja Arumugaswami, Ashok Kumar.Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology. Published February 2, 2024. Accessed April 1, 2024. DOI: 10.1016/j.isci.2024.109088

2. Wayne State University researchers uncover potential treatment targets for Zika virus-related eye abnormalities. EurekAlert! Accessed April 1, 2024. https://www.eurekalert.org/news-releases/1039509