Glycolytic shift during West Nile virus infection provides new therapeutic opportunities
Abstract Background Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medicall...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02899-3 |
| _version_ | 1797557549661159424 |
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| author | Patricia Mingo-Casas Ana-Belén Blázquez Marta Gómez de Cedrón Ana San-Félix Susana Molina Estela Escribano-Romero Eva Calvo-Pinilla Nereida Jiménez de Oya Ana Ramírez de Molina Juan-Carlos Saiz María-Jesús Pérez-Pérez Miguel A. Martín-Acebes |
| author_facet | Patricia Mingo-Casas Ana-Belén Blázquez Marta Gómez de Cedrón Ana San-Félix Susana Molina Estela Escribano-Romero Eva Calvo-Pinilla Nereida Jiménez de Oya Ana Ramírez de Molina Juan-Carlos Saiz María-Jesús Pérez-Pérez Miguel A. Martín-Acebes |
| author_sort | Patricia Mingo-Casas |
| collection | DOAJ |
| description | Abstract Background Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medically relevant neurotropic pathogen causing outbreaks of meningitis and encephalitis worldwide. Results A systematic literature search and meta-analysis pointed to a misbalance of glucose homeostasis in the central nervous system of WNV patients. Real-time bioenergetic analyses confirmed upregulation of aerobic glycolysis and a reduction of mitochondrial oxidative phosphorylation during viral replication in cultured cells. Transcriptomics analyses in neural tissues from experimentally infected mice unveiled a glycolytic shift including the upregulation of hexokinases 2 and 3 (Hk2 and Hk3) and pyruvate dehydrogenase kinase 4 (Pdk4). Treatment of infected mice with the Hk inhibitor, 2-deoxy-D-glucose, or the Pdk4 inhibitor, dichloroacetate, alleviated WNV-induced neuroinflammation. Conclusions These results highlight the importance of host energetic metabolism and specifically glycolysis in WNV infection in vivo. This study provides proof of concept for the druggability of the glycolytic pathway for the future development of therapies to combat WNV pathology. |
| first_indexed | 2024-03-10T17:19:33Z |
| format | Article |
| id | doaj.art-b6f1599544684c47b55688ce4140330e |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:33Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b6f1599544684c47b55688ce4140330e2023-11-20T10:24:18ZengBMCJournal of Neuroinflammation1742-20942023-09-0120111310.1186/s12974-023-02899-3Glycolytic shift during West Nile virus infection provides new therapeutic opportunitiesPatricia Mingo-Casas0Ana-Belén Blázquez1Marta Gómez de Cedrón2Ana San-Félix3Susana Molina4Estela Escribano-Romero5Eva Calvo-Pinilla6Nereida Jiménez de Oya7Ana Ramírez de Molina8Juan-Carlos Saiz9María-Jesús Pérez-Pérez10Miguel A. Martín-Acebes11Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSICInstituto de Quimica Medica (IQM), CSICMolecular Oncology Group, IMDEA Food Institute, CEI UAM + CSICDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSICDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Instituto de Quimica Medica (IQM), CSICDepartment of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas (INIA-CSIC)Abstract Background Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medically relevant neurotropic pathogen causing outbreaks of meningitis and encephalitis worldwide. Results A systematic literature search and meta-analysis pointed to a misbalance of glucose homeostasis in the central nervous system of WNV patients. Real-time bioenergetic analyses confirmed upregulation of aerobic glycolysis and a reduction of mitochondrial oxidative phosphorylation during viral replication in cultured cells. Transcriptomics analyses in neural tissues from experimentally infected mice unveiled a glycolytic shift including the upregulation of hexokinases 2 and 3 (Hk2 and Hk3) and pyruvate dehydrogenase kinase 4 (Pdk4). Treatment of infected mice with the Hk inhibitor, 2-deoxy-D-glucose, or the Pdk4 inhibitor, dichloroacetate, alleviated WNV-induced neuroinflammation. Conclusions These results highlight the importance of host energetic metabolism and specifically glycolysis in WNV infection in vivo. This study provides proof of concept for the druggability of the glycolytic pathway for the future development of therapies to combat WNV pathology.https://doi.org/10.1186/s12974-023-02899-3West Nile virusGlycolysisImmunometabolismNeuroinflammation |
| spellingShingle | Patricia Mingo-Casas Ana-Belén Blázquez Marta Gómez de Cedrón Ana San-Félix Susana Molina Estela Escribano-Romero Eva Calvo-Pinilla Nereida Jiménez de Oya Ana Ramírez de Molina Juan-Carlos Saiz María-Jesús Pérez-Pérez Miguel A. Martín-Acebes Glycolytic shift during West Nile virus infection provides new therapeutic opportunities Journal of Neuroinflammation West Nile virus Glycolysis Immunometabolism Neuroinflammation |
| title | Glycolytic shift during West Nile virus infection provides new therapeutic opportunities |
| title_full | Glycolytic shift during West Nile virus infection provides new therapeutic opportunities |
| title_fullStr | Glycolytic shift during West Nile virus infection provides new therapeutic opportunities |
| title_full_unstemmed | Glycolytic shift during West Nile virus infection provides new therapeutic opportunities |
| title_short | Glycolytic shift during West Nile virus infection provides new therapeutic opportunities |
| title_sort | glycolytic shift during west nile virus infection provides new therapeutic opportunities |
| topic | West Nile virus Glycolysis Immunometabolism Neuroinflammation |
| url | https://doi.org/10.1186/s12974-023-02899-3 |
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