MazF ribonucleases promote Mycobacterium tuberculosis drug tolerance and virulence in guinea pigs

Nat Commun. 2015 Jan 22;6:6059. doi: 10.1038/ncomms7059.

Abstract

Toxin-antitoxin (TA) systems are highly conserved in members of the Mycobacterium tuberculosis (Mtb) complex and have been proposed to play an important role in physiology and virulence. Nine of these TA systems belong to the mazEF family, encoding the intracellular MazF toxin and its antitoxin, MazE. By overexpressing each of the nine putative MazF homologues in Mycobacterium bovis BCG, here we show that Rv1102c (MazF3), Rv1991c (MazF6) and Rv2801c (MazF9) induce bacteriostasis. The construction of various single-, double- and triple-mutant Mtb strains reveals that these MazF ribonucleases contribute synergistically to the ability of Mtb to adapt to conditions such as oxidative stress, nutrient depletion and drug exposure. Moreover, guinea pigs infected with the triple-mutant strain exhibits significantly reduced bacterial loads and pathological damage in infected tissues in comparison with parental strain-infected guinea pigs. The present study highlights the importance of MazF ribonucleases in Mtb stress adaptation, drug tolerance and virulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitoxins / chemistry
  • Antitubercular Agents / chemistry
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / physiology*
  • Disease Models, Animal
  • Disease Progression
  • Drug Resistance, Bacterial
  • Drug Tolerance
  • Endoribonucleases / metabolism
  • Endoribonucleases / physiology*
  • Female
  • Genome, Bacterial
  • Guinea Pigs
  • Kinetics
  • Macrophages / microbiology
  • Mutation
  • Mycobacterium bovis / metabolism
  • Mycobacterium tuberculosis / metabolism*
  • Oxidative Stress
  • Polymerase Chain Reaction
  • Protein Interaction Mapping
  • Ribonucleases / genetics
  • Virulence

Substances

  • Antitoxins
  • Antitubercular Agents
  • Bacterial Proteins
  • Endoribonucleases
  • MazF protein, Mycobacterium tuberculosis
  • Ribonucleases