Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology
Summary: 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,...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224003092 |
| _version_ | 1797302497265582080 |
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| author | Sneha Singh Robert E. Wright, III Shailendra Giri Vaithilingaraja Arumugaswami Ashok Kumar |
| author_facet | Sneha Singh Robert E. Wright, III Shailendra Giri Vaithilingaraja Arumugaswami Ashok Kumar |
| author_sort | Sneha Singh |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-03-07T23:38:39Z |
| format | Article |
| id | doaj.art-c38c56166f024c8b8324af59f96a66ef |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-07T23:38:39Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-c38c56166f024c8b8324af59f96a66ef2024-02-20T04:19:34ZengElsevieriScience2589-00422024-03-01273109088Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathologySneha Singh0Robert E. Wright, III1Shailendra Giri2Vaithilingaraja Arumugaswami3Ashok Kumar4Department of Ophthalmology, Visual and Anatomical Sciences/ Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USADepartment of Ophthalmology, Visual and Anatomical Sciences/ Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USADepartment of Neurology, Henry Ford Health System, Detroit, MI, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USADepartment of Ophthalmology, Visual and Anatomical Sciences/ Kresge Eye Institute, Wayne State University School of Medicine, Detroit, MI, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004224003092VirologyMolecular biology |
| spellingShingle | 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 iScience Virology Molecular biology |
| title | Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology |
| title_full | Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology |
| title_fullStr | Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology |
| title_full_unstemmed | Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology |
| title_short | Targeting ABCG1 and SREBP-2 mediated cholesterol homeostasis ameliorates Zika virus-induced ocular pathology |
| title_sort | targeting abcg1 and srebp 2 mediated cholesterol homeostasis ameliorates zika virus induced ocular pathology |
| topic | Virology Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224003092 |
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