ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection

Cell Microbiol. 2008 Sep;10(9):1866-78. doi: 10.1111/j.1462-5822.2008.01177.x. Epub 2008 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Bacterial Proteins / metabolism*
  • CARD Signaling Adaptor Proteins
  • Calcium / metabolism
  • Carrier Proteins / immunology
  • Caspase 1 / immunology
  • Cells, Cultured
  • Cytoskeletal Proteins / immunology
  • Hemolysis
  • Inflammation / immunology
  • Inflammation / microbiology
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / immunology
  • Interleukin-1beta / biosynthesis
  • Interleukin-1beta / immunology
  • Lysosomes / immunology*
  • Lysosomes / microbiology
  • Macrophage Activation
  • Macrophages / immunology
  • Macrophages / microbiology
  • Macrophages / ultrastructure
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium Infections, Nontuberculous / immunology*
  • Mycobacterium Infections, Nontuberculous / microbiology
  • Mycobacterium marinum / immunology
  • Mycobacterium marinum / pathogenicity*
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / pathogenicity*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phagocytosis*
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology
  • Virulence / genetics
  • Virulence Factors / genetics
  • Virulence Factors / immunology*


  • Apoptosis Regulatory Proteins
  • Bacterial Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Interleukin-18
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse
  • Virulence Factors
  • Caspase 1
  • Calcium