ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria
ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria
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DOI：
10.1111/j.1462-5822.2012.01799.x
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发表时间：
2012-08-01
影响因子：
3.4
通讯作者：
Peters, Peter J.
中科院分区：
文献类型：
--
作者：
Houben, Diane;Demangel, Caroline;Peters, Peter J.
分枝杆菌种类，包括结核分枝杆菌和麻风分枝杆菌，是最强大的人类细菌病原体。细胞质分枝杆菌的发现挑战了这些病原体仅局限于宿主细胞吞噬体的范式。到目前为止，分枝杆菌易位与细胞质的生物学相关性仍不清楚。在目前的研究中，我们使用电子显微镜技术来建立易位和分枝杆菌毒力之间的明确联系。致病性的、患者来源的分枝杆菌物种被发现转移到细胞质，而非致病性的分枝杆菌物种没有。通过将ESX-1 （VII型）分泌系统引入无毒的、完全吞噬溶酶体的牛分枝杆菌BCG，我们进一步能够将细胞质易位与致病性联系起来。此外，我们发现易位依赖于早期分泌抗原ESAT-6的c端。在小鼠中，ESAT-6的c端截断导致衰减，再次将易位与毒性联系起来。总之，这些数据证明了促进分枝杆菌易位的分子机制。从吞噬溶酶体转移到细胞质的能力在本研究中被证明具有重要的生物学意义，因为它决定了分枝杆菌的毒力。
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.