Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47
Abstract
Interferon-γ (IFN-γ) provides an essential component of immunity to tuberculosis by activating infected host macrophages to directly inhibit the replication of Mycobacterium tuberculosis (Mtb). IFN-γ–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-γ–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.
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We thank J. Belisle for provision of purified Mtb cell-wall components; R. Steinman for F4/80 antibody; H. Shio for electron microscopy; D. McMurray for aerosol chamber instruction; P. Giannakis, D. Phelan, R. Rice, and A. Sousa for experimental assistance; and A. Francesconi, A. Muesch, C. Nathan, and members of the Section of Microbial Pathogenesis (Yale University School of Medicine) for helpful discussions. Supported by a Howard Hughes Medical Institute Fellowship of the Life Science Research Foundation (J.D.M.), Veterans Administration Merit Review Grant (G.A.T.), Ellison Medical Foundation, Sequella Global Tuberculosis Foundation, Sinsheimer Fund, Irma T. Hirschl Trust, and NIH RO1 A1051702 (J. D. McKinney).
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Published In
Science
Volume 302 | Issue 5645
24 October 2003
24 October 2003
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American Association for the Advancement of Science.
Submission history
Received: 16 June 2003
Accepted: 27 August 2003
Published in print: 24 October 2003
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