Journal
CELLULAR MICROBIOLOGY
Volume 10, Issue 9, Pages 1866-1878Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1462-5822.2008.01177.x
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Funding
- NIAID NIH HHS [AI55614, R01 AI055614, R01 AI055614-05, AI63302, R01 AI051667, P01 AI063302, AI51667] Funding Source: Medline
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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)-1 beta 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-1 beta and IL-18, dependent on phagocytosis of bacteria containing ESX-1. Synthesis but not release of IL-1 beta 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-1 beta and IL-18. Collectively, these results reveal a role for ESX-1 in triggering secretion of lysosomes, as well as release of IL-1 beta and IL-18 during mycobacteria infection.
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