Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions

被引:177
作者
Conrad, William H. [1 ]
Osman, Morwan M. [1 ,2 ]
Shanahan, Jonathan K. [1 ,3 ]
Chu, Frances [4 ,7 ]
Takaki, Kevin K. [1 ]
Cameron, James [4 ,8 ]
Hopkinson-Woolley, Digby [5 ,9 ]
Brosch, Roland [6 ]
Ramakrishnan, Lalita [1 ,4 ]
机构
[1] Univ Cambridge, Dept Med, Cambridge CB2 0QH, England
[2] Univ Washington, Mol & Cellular Biol Grad Program, Seattle, WA 98105 USA
[3] Univ Cambridge, Wellcome Trust PhD Program Infect Immun & Inflamm, Cambridge CB2 0XY, England
[4] Univ Washington, Dept Microbiol, Seattle, WA 98105 USA
[5] Eton Coll, Dept Biol, Windsor SL4 6DW, England
[6] Inst Pasteur, Unit Integrated Mycobacterial Pathogen, F-75015 Paris, France
[7] InBios Int Inc, Res & Dev, Seattle, WA 98104 USA
[8] NOAA, Environm & Fisheries Sci Div, Seattle, WA 98115 USA
[9] Univ Oxford, St Hildas Coll, Zool, Oxford OX4 1DY, England
基金
英国惠康基金; 美国国家科学基金会; 美国国家卫生研究院;
关键词
Mycobacterium tuberculosis; Mycobacterium marinum; ESAT-6; ESX-1 secretion system; cell membrane lysis; TUBERCULOSIS ESAT-6; VIRULENCE FACTORS; PORE-FORMATION; MARINUM INFECTION; CALMETTE-GUERIN; BOVIS BCG; IFN-GAMMA; IN-VIVO; PROTEIN; ATTENUATION;
D O I
10.1073/pnas.1620133114
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mycobacterium tuberculosis and Mycobacterium marinum are thought to exert virulence, in part, through their ability to lyse host cell membranes. The type VII secretion system ESX-1 [6-kDa early secretory antigenic target (ESAT-6) secretion system 1] is required for both virulence and host cell membrane lysis. Both activities are attributed to the pore-forming activity of the ESX-1-secreted substrate ESAT-6 because multiple studies have reported that recombinant ESAT-6 lyses eukaryotic membranes. We too find ESX-1 of M. tuberculosis and M. marinum lyses host cell membranes. However, we find that recombinant ESAT-6 does not lyse cell membranes. The lytic activity previously attributed to ESAT-6 is due to residual detergent in the preparations. We report here that ESX-1-dependent cell membrane lysis is contact dependent and accompanied by gross membrane disruptions rather than discrete pores. ESX-1-mediated lysis is also morphologically distinct from the contact-dependent lysis of other bacterial secretion systems. Our findings suggest redirection of research to understand the mechanism of ESX-1-mediated lysis.
引用
收藏
页码:1371 / 1376
页数:6
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