Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation

Handle URI:
http://hdl.handle.net/10754/561882
Title:
Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation
Authors:
Abdallah, Abdallah; Bestebroer, Jovanka; Savage, Nigel D L; De Punder, Karin; Van Zon, Maaike; Wilson, Louis D.; Korbee, Cees J.; Van Der Sar, Astrid M.; Ottenhoff, Tom Hm M; Van Der Wel, Nicole N.; Bitter, Wilbert M.; Peters, Peter J.
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-1b 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. Copyright © 2011 by The American Association of Immunologists, Inc.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Publisher:
American Association of Immunologists
Journal:
Journal of Immunology
Issue Date:
28-Sep-2011
DOI:
10.4049/jimmunol.1101457
PubMed ID:
21957139
Type:
Article
ISSN:
00221767
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorAbdallah, Abdallahen
dc.contributor.authorBestebroer, Jovankaen
dc.contributor.authorSavage, Nigel D Len
dc.contributor.authorDe Punder, Karinen
dc.contributor.authorVan Zon, Maaikeen
dc.contributor.authorWilson, Louis D.en
dc.contributor.authorKorbee, Cees J.en
dc.contributor.authorVan Der Sar, Astrid M.en
dc.contributor.authorOttenhoff, Tom Hm Men
dc.contributor.authorVan Der Wel, Nicole N.en
dc.contributor.authorBitter, Wilbert M.en
dc.contributor.authorPeters, Peter J.en
dc.date.accessioned2015-08-03T09:33:14Zen
dc.date.available2015-08-03T09:33:14Zen
dc.date.issued2011-09-28en
dc.identifier.issn00221767en
dc.identifier.pmid21957139en
dc.identifier.doi10.4049/jimmunol.1101457en
dc.identifier.urihttp://hdl.handle.net/10754/561882en
dc.description.abstractDuring 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-1b 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. Copyright © 2011 by The American Association of Immunologists, Inc.en
dc.publisherAmerican Association of Immunologistsen
dc.titleMycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activationen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalJournal of Immunologyen
dc.contributor.institutionNetherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, 1066 CX Amsterdam, Netherlandsen
dc.contributor.institutionDepartment of Medical Microbiology and Infection Control, Free University Medical Center, 1081 BT Amsterdam, Netherlandsen
dc.contributor.institutionDepartment of Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, Netherlandsen
dc.contributor.institutionKavli Institute of Nanoscience, Technical University, 2628 CJ Delft, Netherlandsen
kaust.authorAbdallah, Abdallahen

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