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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Computational Biology
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Disease Susceptibility
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Female
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / physiology
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / physiology*
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Hydrogen-Ion Concentration
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Immunity, Innate
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Interferon-gamma / immunology*
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Macrophage Activation
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages, Alveolar / immunology
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Macrophages, Alveolar / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mutation
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Mycobacterium tuberculosis / growth & development*
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Oligonucleotide Array Sequence Analysis
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Phagosomes / microbiology
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Phagosomes / physiology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Tuberculosis / immunology*
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Tuberculosis / microbiology
Substances
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IFI47 protein, mouse
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Ifi1 protein, mouse
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Interferon-gamma
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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GTP Phosphohydrolases
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GTP-Binding Proteins
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Igtp protein, mouse