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Small molecule control of virulence gene expression in Francisella tularensis

James C Charity1, Leeann T Blalock, Michelle M Costante-Hamm

  • 1Division of Infectious Diseases, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Plos Pathogens
|October 31, 2009
PubMed

Insights

The MglA-SspA complex in Francisella tularensis, along with PigR and ppGpp, regulates virulence genes essential for intramacrophage survival. This interaction controls bacterial growth and virulence in mice.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Bacterial Pathogenesis

Background:

  • Francisella tularensis virulence relies on gene expression controlled by the MglA-SspA complex interacting with RNA polymerase (RNAP).
  • The precise molecular mechanisms of MglA and SspA in regulating virulence gene expression remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which MglA and SspA control virulence gene expression in Francisella tularensis.
  • To identify additional factors interacting with the MglA-SspA complex to regulate virulence.

Main Methods:

  • Genetic analysis of F. tularensis live vaccine strain (LVS) mutants (mglA, sspA, pigR, ppGpp null mutants).
  • Assessment of intramacrophage growth defects and mouse virulence attenuation.
  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Analysis of gene expression regulated by MglA, SspA, PigR, and ppGpp.

Main Results:

  • The MglA-SspA complex collaborates with PigR and guanosine tetraphosphate (ppGpp) to regulate a common set of virulence genes.
  • MglA, SspA, PigR, and ppGpp are all crucial for F. tularensis intramacrophage growth and virulence in mice.
  • PigR directly interacts with the MglA-SspA complex, functioning as a transcription activator target.
  • ppGpp enhances the interaction between PigR and the RNAP-associated MglA-SspA complex, integrating nutritional cues.

Conclusions:

  • The MglA-SspA complex, PigR, and ppGpp form a regulatory network essential for Francisella tularensis virulence.
  • ppGpp acts as a signaling molecule, modulating PigR-MglA-SspA interactions to control virulence gene expression in response to nutritional status.
  • This study reveals a novel regulatory mechanism for bacterial virulence gene expression, integrating environmental cues with transcriptional control.

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