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Updated: Jul 2, 2025
Zika Virus Infectious Cell Culture System and the In Vitro Prophylactic Effect of Interferons
Published on: August 23, 2016
Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology
Sneha Singh1, Robert E Wright1, Shailendra Giri2
1Department of Ophthalmology, Visual and Anatomical Sciences/ Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA.
Insights
Targeting cholesterol metabolism offers a new strategy against Zika virus (ZIKV) eye infections. Enhancing ABCG1 activity or inhibiting SREBP-2 reduced viral replication and disease severity in preclinical models.
Area of Science:
- Virology
- Neuroscience
- Ophthalmology
- Biochemistry
Background:
- Zika virus (ZIKV) infection during pregnancy leads to severe infant neurological and ocular abnormalities.
- Current therapeutic options for ZIKV infection, including vaccines and antivirals, are unavailable.
- Transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed dysregulation in the cholesterol pathway.
Purpose of the Study:
- To investigate the roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREBP-2) in ocular ZIKV infection.
- To explore cholesterol metabolism as a potential therapeutic target for ZIKV-induced ocular disease.
Main Methods:
- In vitro studies using RPE cells to assess ZIKV replication under varying ABCG1 and SREBP-2 activity.
- In vivo studies using a mouse model of ZIKV-induced chorioretinal lesions, treated with LXR agonists or SREBP-2 inhibitors.
- Analysis of viral replication, intracellular cholesterol levels, inflammatory mediators, and antiviral gene expression.
Main Results:
- Increased ABCG1 activity reduced ZIKV replication, while ABCG1 knockdown enhanced it, correlating with intracellular cholesterol levels.
- Inhibition of SREBP-2 reduced ZIKV replication by decreasing cholesterol levels.
- In vivo treatments with LXR agonists or SREBP-2 inhibitors mitigated ZIKV-induced chorioretinal lesions, reduced inflammation, and boosted antiviral responses.
Conclusions:
- ABCG1 exhibits an antiviral role in ocular ZIKV infection, whereas SREBP-2 promotes viral replication.
- Modulating cholesterol metabolism, specifically targeting ABCG1 and SREBP-2, presents a promising therapeutic strategy for ocular ZIKV infections.
Abstract:
Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.
