ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria

Diane Houben, Caroline Demangel, Jakko van Ingen, Jorge Perez, Lucy Baldeón, Abdallah M. Abdallah, Laxmee Caleechurn, Daria Bottai, Maaike van Zon, Karin de Punder, Tridia van der Laan, Arie Kant, Ruth Bossers-de Vries, Peter Willemsen, Wilbert Bitter, Dick van Soolingen, Roland Brosch, Nicole van der Wel, Peter J. Peters, J. van der Laan

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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
Original languageEnglish
Pages (from-to)1287-1298
JournalCellular microbiology
Issue number8
Early online date8 May 2012
Publication statusPublished - 2012

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