title: ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria.
abstract: Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium leprae, are among the most potent human bacterial pathogens. The discovery of cytosolic mycobacteria challenged the paradigm that these pathogens exclusively localize within the phagosome of host cells. As yet the biological relevance of mycobacterial translocation to the cytosol remained unclear. In this current study we used electron microscopy techniques to establish a clear link between translocation and mycobacterial virulence. Pathogenic, patient-derived mycobacteria species were found to translocate to the cytosol, while non-pathogenic species did not. We were further able to link cytosolic translocation with pathogenicity by introducing the ESX-1 (type VII) secretion system into the non-virulent, exclusively phagolysosomal Mycobacterium bovis BCG. Furthermore, we show that translocation is dependent on the C-terminus of the early-secreted antigen ESAT-6. The C-terminal truncation of ESAT-6 was shown to result in attenuation in mice, again linking translocation to virulence. Together, these data demonstrate the molecular mechanism facilitating translocation of mycobacteria. The ability to translocate from the phagolysosome to the cytosol is with this study proven to be biologically significant as it determines mycobacterial virulence.
authors.affiliation: Division of Cell Biology II, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: Houben
authors.forename: Caroline
authors.initials: C
authors.lastname: Demangel
authors.forename: Jakko
authors.initials: J
authors.lastname: van Ingen
authors.forename: Jorge
authors.initials: J
authors.lastname: Perez
authors.forename: Lucy
authors.initials: L
authors.lastname: Baldeón
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Abdallah
authors.forename: Laxmee
authors.initials: L
authors.lastname: Caleechurn
authors.forename: Daria
authors.initials: D
authors.lastname: Bottai
authors.forename: Maaike
authors.initials: M
authors.lastname: van Zon
authors.forename: Karin
authors.initials: K
authors.lastname: de Punder
authors.forename: Tridia
authors.initials: T
authors.lastname: van der Laan
authors.forename: Arie
authors.initials: A
authors.lastname: Kant
authors.forename: Ruth
authors.initials: R
authors.lastname: Bossers-de Vries
authors.forename: Peter
authors.initials: P
authors.lastname: Willemsen
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Nicole
authors.initials: N
authors.lastname: van der Wel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Peters
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000382:microbiology*; D055879:Gene Knock-In Techniques; D054884:Host-Pathogen Interactions; D006801:Humans; D008247:Lysosomes / Q000382:microbiology / Q000648:ultrastructure; D009161:Mycobacterium / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D010588:Phagosomes / Q000382:microbiology / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D025801:Ubiquitin; D037521:Virulence Factors