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Applying an Inducible Expression System to Study Interference of Bacterial Virulence Factors with Intracellular Signaling
08:51

Applying an Inducible Expression System to Study Interference of Bacterial Virulence Factors with Intracellular Signaling

Published on: June 25, 2015

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Glutathione activates virulence gene expression of an intracellular pathogen

Michelle L Reniere1, Aaron T Whiteley2, Keri L Hamilton3

  • 1Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.

Nature
|January 9, 2015
PubMed

Insights

Glutathione, a key molecule in cells, activates the virulence of the intracellular pathogen Listeria monocytogenes. Suppressor mutations bypassed this requirement, revealing glutathione

Area of Science:

  • Microbiology
  • Molecular Biology
  • Pathogenesis

Background:

  • Intracellular pathogens cause significant global disease burden.
  • Pathogen survival within host cells requires environmental sensing and virulence gene regulation.
  • Listeria monocytogenes activates its master virulence regulator, PrfA, upon entering mammalian cells.

Purpose of the Study:

  • To investigate the role of glutathione in activating the virulence regulator PrfA in Listeria monocytogenes.
  • To identify mechanisms by which glutathione influences bacterial virulence gene expression and host colonization.

Main Methods:

  • Genetic selection to identify bacterial mutants with altered virulence.
  • In vivo attenuation studies in a mouse model.
  • Genome sequencing to identify suppressor mutations.
  • Biochemical and genetic assays to elucidate PrfA activation mechanisms.

Main Results:

  • A bacterial mutant deficient in glutathione synthesis showed significantly reduced virulence gene expression and was 150-fold attenuated in mice.
  • Suppressor mutations in prfA restored virulence by creating a constitutively active PrfA* protein, independent of glutathione.
  • Glutathione directly binds allosterically to PrfA, mediating its activation.

Conclusions:

  • Glutathione is essential for activating the virulence regulator PrfA in Listeria monocytogenes.
  • Glutathione acts as a critical signaling molecule for intracellular pathogen virulence.
  • Targeting glutathione-dependent PrfA activation could offer novel therapeutic strategies against Listeria infections.

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