title: Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions.
abstract: 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.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.
authors.forename: William H
authors.initials: WH
authors.lastname: Conrad
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.|Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98105.
authors.forename: Morwan M
authors.initials: MM
authors.lastname: Osman
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.|Wellcome Trust PhD Program in Infection, Immunity, and Inflammation, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Shanahan
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98105.
authors.forename: Frances
authors.initials: F
authors.lastname: Chu
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Takaki
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98105.
authors.forename: James
authors.initials: J
authors.lastname: Cameron
authors.affiliation: Department of Biology, Eton College, Windsor SL4 6DW, United Kingdom.
authors.forename: Digby
authors.initials: D
authors.lastname: Hopkinson-Woolley
authors.affiliation: Unit for Integrated Mycobacterial Pathogenomics, Institut Pasteur, 75015 Paris, France.
authors.forename: Roland
authors.identifier: 0000-0003-2587-3863
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QH, United Kingdom; lr404@cam.ac.uk.|Department of Microbiology, University of Washington, Seattle, WA 98105.
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001422:Bacterial Adhesion; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D058947:Bacterial Secretion Systems / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004910:Erythrocyte Membrane / Q000378:metabolism* / Q000382:microbiology; D004912:Erythrocytes / Q000378:metabolism* / Q000382:microbiology; D006461:Hemolysis; D054884:Host-Pathogen Interactions; D006801:Humans; D007814:Larva / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D019910:Mycobacterium marinum / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D012756:Sheep; D014774:Virulence; D015027:Zebrafish
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; C093276:ESAT-6 protein, Mycobacterium tuberculosis
keywords: ESAT-6; ESX-1 secretion system; Mycobacterium marinum; Mycobacterium tuberculosis; cell membrane lysis