Immune control of tuberculosis by IFN-gamma-inducible LRG-47

Science. 2003 Oct 24;302(5645):654-9. doi: 10.1126/science.1088063.

Abstract

Interferon-gamma (IFN-gamma) provides an essential component of immunity to tuberculosis by activating infected host macrophages to directly inhibit the replication of Mycobacterium tuberculosis (Mtb). IFN-gamma-inducible nitric oxide synthase 2 (NOS2) is considered a principal effector mechanism, although other pathways may also exist. Here, we identify one member of a newly emerging 47-kilodalton (p47) guanosine triphosphatase family, LRG-47, that acts independently of NOS2 to protect against disease. Mice lacking LRG-47 failed to control Mtb replication, unlike those missing the related p47 guanosine triphosphatases IRG-47 or IGTP. Defective bacterial killing in IFN-gamma-activated LRG-47-/- macrophages was associated with impaired maturation of Mtb-containing phagosomes, vesicles that otherwise recruited LRG-47 in wild-type cells. Thus, LRG-47 may serve as a critical vacuolar trafficking component used to dispose of intracellular pathogens like Mtb.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Computational Biology
  • Disease Susceptibility
  • Female
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / physiology
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / physiology*
  • Hydrogen-Ion Concentration
  • Immunity, Innate
  • Interferon-gamma / immunology*
  • Macrophage Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Mycobacterium tuberculosis / growth & development*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Oligonucleotide Array Sequence Analysis
  • Phagosomes / microbiology
  • Phagosomes / physiology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology

Substances

  • IFI47 protein, mouse
  • Ifi1 protein, mouse
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • Igtp protein, mouse