title: Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation.
abstract: During infection of humans and animals, pathogenic mycobacteria manipulate the host cell causing severe diseases such as tuberculosis and leprosy. To understand the basis of mycobacterial pathogenicity, it is crucial to identify the molecular virulence mechanisms. In this study, we address the contribution of ESX-1 and ESX-5--two homologous type VII secretion systems of mycobacteria that secrete distinct sets of immune modulators--during the macrophage infection cycle. Using wild-type, ESX-1- and ESX-5-deficient mycobacterial strains, we demonstrate that these secretion systems differentially affect subcellular localization and macrophage cell responses. We show that in contrast to ESX-1, the effector proteins secreted by ESX-5 are not required for the translocation of Mycobacterium tuberculosis or Mycobacterium marinum to the cytosol of host cells. However, the M. marinum ESX-5 mutant does not induce inflammasome activation and IL-1β activation. The ESX-5 system also induces a caspase-independent cell death after translocation has taken place. Importantly, by means of inhibitory agents and small interfering RNA experiments, we reveal that cathepsin B is involved in both the induction of cell death and inflammasome activation upon infection with wild-type mycobacteria. These results reveal distinct roles for two different type VII secretion systems during infection and shed light on how virulent mycobacteria manipulate the host cell in various ways to replicate and spread.
authors.affiliation: The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Abdallah
authors.forename: Jovanka
authors.initials: J
authors.lastname: Bestebroer
authors.forename: Nigel D L
authors.initials: ND
authors.lastname: Savage
authors.forename: Karin
authors.initials: K
authors.lastname: de Punder
authors.forename: Maaike
authors.initials: M
authors.lastname: van Zon
authors.forename: Louis
authors.initials: L
authors.lastname: Wilson
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Korbee
authors.forename: Astrid M
authors.initials: AM
authors.lastname: van der Sar
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Nicole N
authors.initials: NN
authors.lastname: van der Wel
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D019910:Mycobacterium marinum / Q000276:immunology* / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C432969:ESX1 protein, human; C107475:Esx1 protein, mouse; D018398:Homeodomain Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D026901:Membrane Transport Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors