Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity

PLoS Pathog. 2013;9(10):e1003678. doi: 10.1371/journal.ppat.1003678. Epub 2013 Oct 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alphavirus Infections / drug therapy
  • Alphavirus Infections / genetics
  • Alphavirus Infections / immunology
  • Alphavirus Infections / metabolism*
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Chikungunya Fever
  • Chikungunya virus / genetics
  • Chikungunya virus / immunology
  • Chikungunya virus / metabolism*
  • Chlorocebus aethiops
  • HeLa Cells
  • Humans
  • Immunity, Innate / drug effects*
  • Immunity, Innate / immunology
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / immunology
  • Interferon Regulatory Factor-1 / metabolism
  • Pyrimidines / biosynthesis*
  • Pyrimidines / immunology
  • Vero Cells

Substances

  • Antiviral Agents
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Pyrimidines
  • pyrimidine

Grant support

This work was supported by the Institut Pasteur (www.pasteur.fr), the Centre National de la Recherche Scientifique (CNRS; www.cnrs.fr), the Institut National de la Santé Et de la Recherche Médicale (INSERM; www.inserm.fr), the Institut Carnot – Pasteur Maladies Infectieuses (Programme STING to POV and HML), the Agence Nationale pour la Recherche (ANR-RPIB, Programme STING 2.0 to POV), and the “Conseil Régional d'Ile-de-France” (Chemical Library Project, grants n° I 06-222/R and I 09-1739/R to HML). The work on CHIKV/Ren was supported by the project ArbOAS (ANR grant 2010-INTB-1601-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.