Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity.
Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/50f5357168b6455188060f26593ac8fd |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:50f5357168b6455188060f26593ac8fd |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:50f5357168b6455188060f26593ac8fd2021-11-18T06:07:34ZInhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity.1553-73661553-737410.1371/journal.ppat.1003678https://doaj.org/article/50f5357168b6455188060f26593ac8fd2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24098125/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response.Marianne Lucas-HouraniDaniel DauzonnePierre JordaGaëlle CousinAlexandru LupanOlivier HelynckGrégory CaignardGeneviève JanvierGwénaëlle André-LerouxSamira KhiarNicolas EscriouPhilippe DesprèsYves JacobHélène Munier-LehmannFrédéric TangyPierre-Olivier VidalainPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 10, p e1003678 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Marianne Lucas-Hourani Daniel Dauzonne Pierre Jorda Gaëlle Cousin Alexandru Lupan Olivier Helynck Grégory Caignard Geneviève Janvier Gwénaëlle André-Leroux Samira Khiar Nicolas Escriou Philippe Desprès Yves Jacob Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| description |
Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response. |
| format |
article |
| author |
Marianne Lucas-Hourani Daniel Dauzonne Pierre Jorda Gaëlle Cousin Alexandru Lupan Olivier Helynck Grégory Caignard Geneviève Janvier Gwénaëlle André-Leroux Samira Khiar Nicolas Escriou Philippe Desprès Yves Jacob Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain |
| author_facet |
Marianne Lucas-Hourani Daniel Dauzonne Pierre Jorda Gaëlle Cousin Alexandru Lupan Olivier Helynck Grégory Caignard Geneviève Janvier Gwénaëlle André-Leroux Samira Khiar Nicolas Escriou Philippe Desprès Yves Jacob Hélène Munier-Lehmann Frédéric Tangy Pierre-Olivier Vidalain |
| author_sort |
Marianne Lucas-Hourani |
| title |
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| title_short |
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| title_full |
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| title_fullStr |
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| title_full_unstemmed |
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| title_sort |
inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/50f5357168b6455188060f26593ac8fd |
| work_keys_str_mv |
AT mariannelucashourani inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT danieldauzonne inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT pierrejorda inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT gaellecousin inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT alexandrulupan inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT olivierhelynck inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT gregorycaignard inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT genevievejanvier inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT gwenaelleandreleroux inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT samirakhiar inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT nicolasescriou inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT philippedespres inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT yvesjacob inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT helenemunierlehmann inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT frederictangy inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity AT pierreoliviervidalain inhibitionofpyrimidinebiosynthesispathwaysuppressesviralgrowththroughinnateimmunity |
| _version_ |
1718424536522686464 |