Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity
Autor(es): Lucas-Hourani Marianne, Dauzonne Daniel, Jorda Pierre, Cousin Gaëlle, Lupan Alexandru, Helynck Olivier, Caignard Grégory, Janvier Geneviève, André-Leroux Gwénaëlle, Khiar Samira, Escriou Nicolas, Desprès Philippe, Jacob Yves, Munier-Lehmann Hélène, Tangy Frédéric, Vidalain Pierre-Olivier
Resumo: 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 - 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, - 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.
Imprenta: PLoS Pathogens, v. 9, n. 10, p. e1003678, 2013
Identificador do objeto digital: 10.1371/journal.ppat.1003678
Descritores: Chikungunya virus - Biosynthesis ; Chikungunya virus - Cell ; Chikungunya virus - Immune response ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Protein synthesis ; Chikungunya virus - Proteins ; Chikungunya virus - Immune response ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Immunology
Data de publicação: 2013
