Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains
Identifieur interne : 000A39 ( Main/Exploration ); précédent : 000A38; suivant : 000A40Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains
Auteurs : Christopher D. Intemann [Allemagne] ; Thorsten Thye [Allemagne] ; Stefan Niemann [Allemagne] ; Edmund N. L. Browne [Ghana] ; Margaret Amanua Chinbuah [Ghana] ; Anthony Enimil [Ghana] ; John Gyapong [Ghana] ; Ivy Osei [Ghana] ; Ellis Owusu-Dabo [Ghana] ; Susanne Helm [Allemagne] ; Sabine Rüsch-Gerdes [Allemagne] ; Rolf D. Horstmann [Allemagne] ; Christian G. Meyer [Allemagne]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2009.
Abstract
The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens
Url:
DOI: 10.1371/journal.ppat.1000577
PubMed: 19750224
PubMed Central: 2735778
Affiliations:
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Intemann</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Thye, Thorsten" sort="Thye, Thorsten" uniqKey="Thye T" first="Thorsten" last="Thye">Thorsten Thye</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Niemann, Stefan" sort="Niemann, Stefan" uniqKey="Niemann S" first="Stefan" last="Niemann">Stefan Niemann</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>National Reference Center for Mycobacteria, Research Center Borstel, Borstel</wicri:regionArea><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion></affiliation></author><author><name sortKey="Browne, Edmund N L" sort="Browne, Edmund N L" uniqKey="Browne E" first="Edmund N. 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Intemann</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Thye, Thorsten" sort="Thye, Thorsten" uniqKey="Thye T" first="Thorsten" last="Thye">Thorsten Thye</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck</wicri:regionArea><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion><wicri:noRegion>Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Niemann, Stefan" sort="Niemann, Stefan" uniqKey="Niemann S" first="Stefan" last="Niemann">Stefan Niemann</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>National Reference Center for Mycobacteria, Research Center Borstel, Borstel</wicri:regionArea><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion></affiliation></author><author><name sortKey="Browne, Edmund N L" sort="Browne, Edmund N L" uniqKey="Browne E" first="Edmund N. L." last="Browne">Edmund N. L. Browne</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Amanua Chinbuah, Margaret" sort="Amanua Chinbuah, Margaret" uniqKey="Amanua Chinbuah M" first="Margaret" last="Amanua Chinbuah">Margaret Amanua Chinbuah</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Health Research Unit, Ghana Health Service, Accra, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Health Research Unit, Ghana Health Service, Accra</wicri:regionArea><placeName><settlement type="city">Accra</settlement><region nuts="2">Région du Grand Accra</region></placeName></affiliation></author><author><name sortKey="Enimil, Anthony" sort="Enimil, Anthony" uniqKey="Enimil A" first="Anthony" last="Enimil">Anthony Enimil</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Komfo Anokye Teaching Hospital, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Komfo Anokye Teaching Hospital, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Gyapong, John" sort="Gyapong, John" uniqKey="Gyapong J" first="John" last="Gyapong">John Gyapong</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Health Research Unit, Ghana Health Service, Accra, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Health Research Unit, Ghana Health Service, Accra</wicri:regionArea><placeName><settlement type="city">Accra</settlement><region nuts="2">Région du Grand Accra</region></placeName></affiliation></author><author><name sortKey="Osei, Ivy" sort="Osei, Ivy" uniqKey="Osei I" first="Ivy" last="Osei">Ivy Osei</name><affiliation wicri:level="3"><nlm:aff id="aff5"><addr-line>Health Research Unit, Ghana Health Service, Accra, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Health Research Unit, Ghana Health Service, Accra</wicri:regionArea><placeName><settlement type="city">Accra</settlement><region nuts="2">Région du Grand Accra</region></placeName></affiliation></author><author><name sortKey="Owusu Dabo, Ellis" sort="Owusu Dabo, Ellis" uniqKey="Owusu Dabo E" first="Ellis" last="Owusu-Dabo">Ellis Owusu-Dabo</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi</wicri:regionArea><wicri:noRegion>Kumasi</wicri:noRegion></affiliation></author><author><name sortKey="Helm, Susanne" sort="Helm, Susanne" uniqKey="Helm S" first="Susanne" last="Helm">Susanne Helm</name><affiliation wicri:level="3"><nlm:aff id="aff8"><addr-line>Department of Parasitology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Parasitology, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Rusch Gerdes, Sabine" sort="Rusch Gerdes, Sabine" uniqKey="Rusch Gerdes S" first="Sabine" last="Rüsch-Gerdes">Sabine Rüsch-Gerdes</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>National Reference Center for Mycobacteria, Research Center Borstel, Borstel</wicri:regionArea><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion><wicri:noRegion>Borstel</wicri:noRegion></affiliation></author><author><name sortKey="Horstmann, Rolf D" sort="Horstmann, Rolf D" uniqKey="Horstmann R" first="Rolf D." last="Horstmann">Rolf D. Horstmann</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author><author><name sortKey="Meyer, Christian G" sort="Meyer, Christian G" uniqKey="Meyer C" first="Christian G." last="Meyer">Christian G. Meyer</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens <italic>in vitro</italic>. This includes <italic>Mycobacterium tuberculosis</italic>, which is in agreement with findings indicating that <italic>M. tuberculosis</italic> translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied <italic>IRGM</italic> gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS<italic>6110</italic> fingerprinting and genotyping of the <italic>pks1/15</italic> deletion. The <italic>IRGM</italic> genotype −261TT was negatively associated with TB caused by <italic>M. tuberculosis</italic> (OR 0.66, CI 0.52–0.84, P<sub>nominal</sub> 0.0009, P<sub>corrected</sub> 0.0045) and not with TB caused by <italic>M. africanum</italic> or <italic>M. bovis</italic> (OR 0.95, CI 0.70–1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to <italic>M. tuberculosis</italic> strains with a damaged <italic>pks1/15</italic> gene which is characteristic for the Euro-American (EUAM) subgroup of <italic>M. tuberculosis</italic> (OR 0.63, CI 0.49–0.81, P<sub>nominal</sub> 0.0004, P<sub>corrected</sub> 0.0019). Our results, including those of luciferase reporter gene assays with the <italic>IRGM</italic> variants −261C and −261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with <italic>M. tuberculosis</italic> EUAM clades. Moreover, they support <italic>in vitro</italic> findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact <italic>pks1/15</italic> gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the <italic>IRGM</italic> −261TT genotype may have contributed to the establishment of <italic>M. africanum</italic> as a pathogen in the West African population.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Deretic, V" uniqKey="Deretic V">V Deretic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walker, S" uniqKey="Walker S">S Walker</name></author><author><name sortKey="Chandra, P" uniqKey="Chandra P">P Chandra</name></author><author><name sortKey="Manifava, M" uniqKey="Manifava M">M Manifava</name></author><author><name sortKey="Axe, E" uniqKey="Axe E">E Axe</name></author><author><name sortKey="Ktistakis, Nt" uniqKey="Ktistakis N">NT Ktistakis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gutierrez, Mg" uniqKey="Gutierrez M">MG Gutierrez</name></author><author><name sortKey="Master, 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Niemann</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Allemagne</li><li>Ghana</li></country><region><li>Hambourg</li><li>Région du Grand Accra</li></region><settlement><li>Accra</li><li>Hambourg</li></settlement></list><tree><country name="Allemagne"><region name="Hambourg"><name sortKey="Intemann, Christopher D" sort="Intemann, Christopher D" uniqKey="Intemann C" first="Christopher D." last="Intemann">Christopher D. Intemann</name></region><name sortKey="Helm, Susanne" sort="Helm, Susanne" uniqKey="Helm S" first="Susanne" last="Helm">Susanne Helm</name><name sortKey="Horstmann, Rolf D" sort="Horstmann, Rolf D" uniqKey="Horstmann R" first="Rolf D." last="Horstmann">Rolf D. Horstmann</name><name sortKey="Intemann, Christopher D" sort="Intemann, Christopher D" uniqKey="Intemann C" first="Christopher D." last="Intemann">Christopher D. Intemann</name><name sortKey="Meyer, Christian G" sort="Meyer, Christian G" uniqKey="Meyer C" first="Christian G." last="Meyer">Christian G. Meyer</name><name sortKey="Niemann, Stefan" sort="Niemann, Stefan" uniqKey="Niemann S" first="Stefan" last="Niemann">Stefan Niemann</name><name sortKey="Rusch Gerdes, Sabine" sort="Rusch Gerdes, Sabine" uniqKey="Rusch Gerdes S" first="Sabine" last="Rüsch-Gerdes">Sabine Rüsch-Gerdes</name><name sortKey="Thye, Thorsten" sort="Thye, Thorsten" uniqKey="Thye T" first="Thorsten" last="Thye">Thorsten Thye</name><name sortKey="Thye, Thorsten" sort="Thye, Thorsten" uniqKey="Thye T" first="Thorsten" last="Thye">Thorsten Thye</name></country><country name="Ghana"><noRegion><name sortKey="Browne, Edmund N L" sort="Browne, Edmund N L" uniqKey="Browne E" first="Edmund N. L." last="Browne">Edmund N. L. Browne</name></noRegion><name sortKey="Amanua Chinbuah, Margaret" sort="Amanua Chinbuah, Margaret" uniqKey="Amanua Chinbuah M" first="Margaret" last="Amanua Chinbuah">Margaret Amanua Chinbuah</name><name sortKey="Enimil, Anthony" sort="Enimil, Anthony" uniqKey="Enimil A" first="Anthony" last="Enimil">Anthony Enimil</name><name sortKey="Enimil, Anthony" sort="Enimil, Anthony" uniqKey="Enimil A" first="Anthony" last="Enimil">Anthony Enimil</name><name sortKey="Gyapong, John" sort="Gyapong, John" uniqKey="Gyapong J" first="John" last="Gyapong">John Gyapong</name><name sortKey="Osei, Ivy" sort="Osei, Ivy" uniqKey="Osei I" first="Ivy" last="Osei">Ivy Osei</name><name sortKey="Owusu Dabo, Ellis" sort="Owusu Dabo, Ellis" uniqKey="Owusu Dabo E" first="Ellis" last="Owusu-Dabo">Ellis Owusu-Dabo</name><name sortKey="Owusu Dabo, Ellis" sort="Owusu Dabo, Ellis" uniqKey="Owusu Dabo E" first="Ellis" last="Owusu-Dabo">Ellis Owusu-Dabo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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