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Science 302 (5645): 654-659

Copyright © 2003 by the American Association for the Advancement of Science

Immune Control of Tuberculosis by IFN-{gamma}-Inducible LRG-47

John D. MacMicking,1* Gregory A. Taylor,2,3 John D. McKinney1

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.

1 Laboratory of Infection Biology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
2 Department of Medicine, Department of Immunology, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC 27705, USA.
3 Geriatric Research, Education, and Clinical Center, Durham Veterans Administration Medical Center, Durham, NC 27705, USA.

* To whom correspondence should be addressed. E-mail: macmicj{at}mail.rockefeller.edu

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The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis.
C. Holscher, A. Holscher, D. Ruckerl, T. Yoshimoto, H. Yoshida, T. Mak, C. Saris, and S. Ehlers (2005)
J. Immunol. 174, 3534-3544
   Abstract »    Full Text »    PDF »
Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis.
I. Vergne, J. Chua, H.-H. Lee, M. Lucas, J. Belisle, and V. Deretic (2005)
PNAS 102, 4033-4038
   Abstract »    Full Text »    PDF »
Phagosomal Processing of Mycobacterium tuberculosis Antigen 85B Is Modulated Independently of Mycobacterial Viability and Phagosome Maturation.
L. Ramachandra, J. L. Smialek, S. S. Shank, M. Convery, W. H. Boom, and C. V. Harding (2005)
Infect. Immun. 73, 1097-1105
   Abstract »    Full Text »    PDF »
A Proteomic Analysis of Lysosomal Integral Membrane Proteins Reveals the Diverse Composition of the Organelle.
R. D. Bagshaw, D. J. Mahuran, and J. W. Callahan (2005)
Mol. Cell. Proteomics 4, 133-143
   Abstract »    Full Text »    PDF »
S-nitroso proteome of Mycobacterium tuberculosis: Enzymes of intermediary metabolism and antioxidant defense.
K. Y. Rhee, H. Erdjument-Bromage, P. Tempst, and C. F. Nathan (2005)
PNAS 102, 467-472
   Abstract »    Full Text »    PDF »
Replication Dynamics of Mycobacterium tuberculosis in Chronically Infected Mice.
E. J. Munoz-Elias, J. Timm, T. Botha, W.-T. Chan, J. E. Gomez, and J. D. McKinney (2005)
Infect. Immun. 73, 546-551
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IL-27 Signaling Compromises Control of Bacterial Growth in Mycobacteria-Infected Mice.
J. E. Pearl, S. A. Khader, A. Solache, L. Gilmartin, N. Ghilardi, F. deSauvage, and A. M. Cooper (2004)
J. Immunol. 173, 7490-7496
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Evaluation of an In Vitro Assay for Gamma Interferon Production in Response to Mycobacterium tuberculosis Infections.
E. W. Taggart, H. R. Hill, R. G. Ruegner, T. B. Martins, and C. M. Litwin (2004)
Clin. Vaccine Immunol. 11, 1089-1093
   Abstract »    Full Text »    PDF »
Prolonged Toll-Like Receptor Signaling by Mycobacterium tuberculosis and Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages.
R. K. Pai, M. E. Pennini, A. A. R. Tobian, D. H. Canaday, W. H. Boom, and C. V. Harding (2004)
Infect. Immun. 72, 6603-6614
   Abstract »    Full Text »    PDF »
Human RAS Superfamily Proteins and Related GTPases.
J. Colicelli (2004)
Sci. STKE 2004, re13
   Abstract »    Full Text »    PDF »
Identification of Mycobacterium tuberculosis Counterimmune (cim) Mutants in Immunodeficient Mice by Differential Screening.
K. B. Hisert, M. A. Kirksey, J. E. Gomez, A. O. Sousa, J. S. Cox, W. R. Jacobs Jr., C. F. Nathan, and J. D. McKinney (2004)
Infect. Immun. 72, 5315-5321
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Mechanisms Regulating the Positioning of Mouse p47 Resistance GTPases LRG-47 and IIGP1 on Cellular Membranes: Retargeting to Plasma Membrane Induced by Phagocytosis.
S. Martens, K. Sabel, R. Lange, R. Uthaiah, E. Wolf, and J. C. Howard (2004)
J. Immunol. 173, 2594-2606
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Mice Deficient in LRG-47 Display Increased Susceptibility to Mycobacterial Infection Associated with the Induction of Lymphopenia.
C. G. Feng, C. M. Collazo-Custodio, M. Eckhaus, S. Hieny, Y. Belkaid, K. Elkins, D. Jankovic, G. A. Taylor, and A. Sher (2004)
J. Immunol. 172, 1163-1168
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Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients.
J. Timm, F. A. Post, L.-G. Bekker, G. B. Walther, H. C. Wainwright, R. Manganelli, W.-T. Chan, L. Tsenova, B. Gold, I. Smith, et al. (2003)
PNAS 100, 14321-14326
   Abstract »    Full Text »    PDF »

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