Immune control of tuberculosis by IFN-gamma-inducible LRG-47.
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.
Laboratory of Infection Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. macmicj@mail.rockefeller.edu
John D
JD
MacMicking
Gregory A
GA
Taylor
John D
JD
McKinney
D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D004198:Disease Susceptibility; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020411:Oligonucleotide Array Sequence Analysis; D010588:Phagosomes / Q000382:microbiology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
C102949:IFI47 protein, mouse; C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C101131:Igtp protein, mouse