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The role of relA and spoT in Yersinia pestis KIM5 pathogenicity

Wei Sun1, Kenneth L Roland, Christine G Branger

  • 1Center for Infectious Disease and Vaccinology, The Biodesign Institute and School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America.

Plos One
|August 25, 2009
PubMed

Insights

The study shows that the molecule guanosine tetraphosphate (ppGpp) is crucial for Yersinia pestis virulence. A mutant lacking ppGpp synthesis was less virulent and showed promise as a plague vaccine candidate.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Immunology

Background:

  • The stringent response molecule guanosine tetraphosphate (ppGpp) regulates bacterial growth and virulence.
  • Yersinia pestis, the plague pathogen, utilizes conserved regulatory systems to adapt to host environments.
  • Understanding ppGpp's role is key to developing novel strategies against Y. pestis.

Purpose of the Study:

  • To investigate the function of ppGpp in Yersinia pestis.
  • To determine the impact of ppGpp deficiency on Y. pestis growth, virulence, and host immune response.
  • To evaluate a ppGpp-deficient Y. pestis mutant as a potential vaccine.

Main Methods:

  • Construction of a double mutant (Delta relA Delta spoT) in Y. pestis unable to synthesize ppGpp.
  • Phenotypic characterization of the mutant, including growth rate, autoaggregation, and virulence protein secretion.
  • Assessment of mutant virulence in a mouse model and evaluation of its vaccine potential.

Main Results:

  • The Delta relA Delta spoT mutant failed to synthesize ppGpp under starvation conditions and exhibited reduced growth and altered autoaggregation.
  • Mutant strains showed significantly decreased secretion of key Y. pestis virulence factors.
  • The ppGpp-deficient mutant was over 1,000-fold less virulent than wild-type Y. pestis.
  • Vaccination with the mutant conferred significant protection against Y. pestis challenge in mice.

Conclusions:

  • ppGpp is a critical determinant of Yersinia pestis virulence.
  • The Delta relA Delta spoT mutant is a promising candidate for a live attenuated plague vaccine.
  • Targeting the ppGpp synthesis pathway could offer new therapeutic avenues against Y. pestis infections.

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