Cited by 685Tuberculosis Research and EpidemiologyImmune responses and vaccinationsImmune Response and Inflammation

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Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47

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MacMicking, John D., Taylor, Gregory A., McKinney, John D.·2003·Science

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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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Authors: MacMicking, J. D., Taylor, G. A., & McKinney, J. D.
Affiliations: Duke University (US)
Corresponding author: MacMicking, John D.
ORCID: MacMicking, John D.
Taylor, Gregory A.
McKinney, John D.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2003-10-24
Volume: 302
Issue: 5645
Pages: 654-659
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1088063
OpenAlex: W1989883893
Cited by: 685
References: 31
Citations by year: 2026: 11 · 2025: 15 · 2024: 16 · 2023: 21 · 2022: 15 · 2021: 27 · 2020: 23 · 2019: 26 · 2018: 27 · 2017: 21 · 2016: 21 · 2015: 34 · 2014: 31 · 2013: 44 · 2012: 44
FWCI: 19.81
Type: journal article
Language: en
Open access: green
infoscience.epfl.ch
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders: U.S. Public Health Service (R01 A1051702)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: tuberculosis, interferon-gamma, Mycobacterium tuberculosis, nitric oxide synthase 2, intracellular pathogen clearance, vacuolar trafficking, host immunity
MeSH terms: Animals, Cells, Cultured, Disease Susceptibility, Female, Hydrogen-Ion Concentration, Immunity, Innate, Interferon-gamma, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Phagosomes, Tuberculosis, Signal Transduction, Macrophages, Alveolar, Nitric Oxide Synthase, GTP-Binding Proteins, Computational Biology, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, GTP Phosphohydrolases, Mice, Nitric Oxide Synthase Type II

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Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47

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