Host-detrimental role of Esx-1-mediated inflammasome activation in mycobacterial infection.
The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1beta, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome.
Carlsson
Fredric
F
Department of Microbial Pathogenesis, Genentech Inc., South San Francisco, California, USA. fredric.carlsson@ki.se
Kim
Janice
J
Dumitru
Calin
C
Barck
Kai H
KH
Carano
Richard A D
RA
Sun
Mei
M
Diehl
Lauri
L
Brown
Eric J
EJ
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology* / Q000382:microbiology; D019910:Mycobacterium marinum / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010588:Phagosomes / Q000276:immunology; D013623:Tail / Q000382:microbiology; D014375:Tuberculoma / Q000276:immunology / Q000382:microbiology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D037521:Virulence Factors
Genome Res. 2008 May;18(5):729-41
18403782
Nat Rev Immunol. 2007 Jan;7(1):31-40
17186029
FEMS Immunol Med Microbiol. 1999 Feb;23(2):149-58
10076912
Am J Respir Crit Care Med. 1996 Feb;153(2):799-804
8564135
J Immunol. 2006 Jul 1;177(1):437-42
16785540
Arch Pathol Lab Med. 1985 Dec;109(12):1109-13
3840985
PLoS Biol. 2004 Nov;2(11):e367
15510227
Annu Rev Microbiol. 2003;57:641-76
14527294
J Immunol. 2001 Jun 15;166(12):7033-41
11390447
Mol Microbiol. 2004 Jan;51(2):359-70
14756778
Microbes Infect. 2006 Apr;8(4):1179-88
16513383
Annu Rev Immunol. 2004;22:599-623
15032590
Nat Rev Microbiol. 2007 Nov;5(11):883-91
17922044
J Pathol. 2006 Jan;208(2):261-9
16362982
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11786-91
8876215
Cell Microbiol. 2008 Sep;10(9):1866-78
18503637
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15190-5
10611360
Cell. 2009 Jan 9;136(1):37-49
19135887
Infect Immun. 2009 Sep;77(9):3992-4001
19596775
Arthritis Rheum. 2004 Oct;50(10):3377-86
15476252
Immunogenetics. 2007 Oct;59(10):761-78
17874090
Nat Rev Microbiol. 2007 Jan;5(1):39-47
17160001
Immunity. 2008 Aug 15;29(2):283-94
18691913
J Exp Med. 2003 Nov 3;198(9):1361-8
14597736
Curr Biol. 2006 Oct 24;16(20):1977-85
17055976
Eur J Immunol. 2009 Jul;39(7):1914-22
19544485
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13001-6
14557536
Curr Opin Immunol. 2004 Aug;16(4):499-505
15245746
Mol Microbiol. 2004 Sep;53(6):1677-93
15341647
J Bacteriol. 1967 Mar;93(3):790-6
5337835
J Bacteriol. 1963 Nov;86:1057-69
14080772
Science. 2010 Jan 22;327(5964):466-9
20007864
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):710-5
18180457
Cell Host Microbe. 2008 Apr 17;3(4):224-32
18407066
Nat Immunol. 2004 Aug;5(8):828-35
15220915
J Immunol. 2007 Aug 15;179(4):2509-19
17675513
J Leukoc Biol. 2007 Aug;82(2):259-64
17470531
Mol Microbiol. 2002 Nov;46(3):709-17
12410828
Infect Immun. 1999 May;67(5):2585-9
10225924
J Immunol. 2007 Mar 1;178(5):3143-52
17312162
Blood. 2007 Jun 1;109(11):4846-55
17289816
J Immunol. 2002 Jul 1;169(1):323-9
12077261
Eur J Immunol. 2006 Jun;36(6):1443-52
16673446
Cell. 2007 Jun 29;129(7):1287-98
17604718
J Immunol. 2004 Oct 15;173(8):4936-44
15470035
Cell Microbiol. 2007 Jun;9(6):1376-84
17466013
Cell Microbiol. 2007 Jun;9(6):1547-55
17298391