The Mycobacterium tuberculosis SecA2 system subverts phagosome maturation to promote growth in macrophages

Infect Immun. 2012 Mar;80(3):996-1006. doi: 10.1128/IAI.05987-11. Epub 2012 Jan 3.

Abstract

The ability of Mycobacterium tuberculosis to grow in macrophages is critical to the virulence of this important pathogen. One way M. tuberculosis is thought to maintain a hospitable niche in macrophages is by arresting the normal process of phagosomes maturing into acidified phagolysosomes. The process of phagosome maturation arrest by M. tuberculosis is not fully understood, and there has remained a need to firmly establish a requirement for phagosome maturation arrest for M. tuberculosis growth in macrophages. Other intracellular pathogens that control the phagosomal environment use specialized protein export systems to deliver effectors of phagosome trafficking to the host cell. In M. tuberculosis, the accessory SecA2 system is a specialized protein export system that is required for intracellular growth in macrophages. In studying the importance of the SecA2 system in macrophages, we discovered that SecA2 is required for phagosome maturation arrest. Shortly after infection, phagosomes containing a ΔsecA2 mutant of M. tuberculosis were more acidified and showed greater association with markers of late endosomes than phagosomes containing wild-type M. tuberculosis. We further showed that inhibitors of phagosome acidification rescued the intracellular growth defect of the ΔsecA2 mutant, which demonstrated that the phagosome maturation arrest defect of the ΔsecA2 mutant is responsible for the intracellular growth defect. This study demonstrates the importance of phagosome maturation arrest for M. tuberculosis growth in macrophages, and it suggests there are effectors of phagosome maturation that are exported into the host environment by the accessory SecA2 system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Gene Deletion
  • Host-Pathogen Interactions*
  • Immune Evasion*
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / pathogenicity*
  • Phagosomes / immunology
  • Phagosomes / microbiology*
  • Virulence Factors / genetics
  • Virulence Factors / metabolism*

Substances

  • Bacterial Proteins
  • Membrane Transport Proteins
  • Virulence Factors
  • Adenosine Triphosphatases
  • SecA2 protein, Mycobacterium