title: ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection.
abstract: Exocytosis of lysosomes from macrophages has been described as a response to microbial cytotoxins and haemolysins, as well as for releasing pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 during inflammasome activation. The mycobacterial ESX-1 secretion system, encoded in part by the Region of Difference-1, is a virulence factor necessary for phagosome escape and host cell lysis by a contact-dependent haemolysin in Mycobacterium marinum. Here we show that ESX-1 from M. marinum and M. tuberculosis is required for Ca(2+)-dependent induction of lysosome secretion from macrophages. Mycobacteria-induced lysosome secretion was concurrent to release of IL-1beta and IL-18, dependent on phagocytosis of bacteria containing ESX-1. Synthesis but not release of IL-1beta and IL-18 occurred in response to dead bacilli and bacteria lacking ESX-1, indicating that only cytokine release was regulated by ESX-1. Release of these cytokines and exocytosis of lysosomes were independent of intracellular mycobacterial growth, yet correlated with mycobacteria-encoded haemolytic activity, demonstrating a parallel pathway for the two responses. We further identified inflammasome components caspase-1, ASC and NALP3, but not Ipaf, required for release of IL-1beta and IL-18. Collectively, these results reveal a role for ESX-1 in triggering secretion of lysosomes, as well as release of IL-1beta and IL-18 during mycobacteria infection.
authors.affiliation: Program in Microbial Pathogenesis and Host Defense, University of California, San Fancisco, CA, USA.
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Koo
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Sridharan
authors.initials: S
authors.lastname: Raghavan
authors.forename: J Hiroshi
authors.initials: JH
authors.lastname: Morisaki
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000276:immunology; D006461:Hemolysis; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D008247:Lysosomes / Q000276:immunology* / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum / Q000276:immunology / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010587:Phagocytosis; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D037521:Virulence Factors; D020170:Caspase 1; D002118:Calcium