Nucleotide-binding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis.
Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. NOD2 has recently been shown to be important for host cell cytokine responses to Mycobacterium tuberculosis, to synergize with Toll-like receptor 2 (TLR2) in mediating these responses, and thus to serve as a nonredundant recognition receptor for M. tuberculosis. Here, we demonstrate that macrophages and dendritic cells from NOD2-deficient mice were impaired in the production of proinflammatory cytokines and nitric oxide following infection with live, virulent M. tuberculosis. Mycolylarabinogalactan peptidoglycan (PGN), the cell wall core of M. tuberculosis, stimulated macrophages to release tumor necrosis factor (TNF) and interleukin-12p40 in a partially NOD2-dependent manner, and M. tuberculosis PGN required NOD2 for the optimal induction of TNF. However, NOD2-deficient mice were no more susceptible to infection with virulent M. tuberculosis than wild-type mice: they controlled the replication of M. tuberculosis in lung, spleen, and liver as well as wild-type mice, and both genotypes displayed similar lung pathologies. In addition, mice doubly deficient for NOD2 and TLR2 were similarly able to control an M. tuberculosis infection. Thus, NOD2 appears to participate in the recognition of M. tuberculosis by antigen-presenting cells in vitro yet is dispensable for the control of the pathogen during in vivo infection.
Gandotra
Sheetal
S
Department of Microbiology and Immunology, Weill Cornell Medical College, Box 62, 1300 York Avenue, New York, NY 10021, USA.
Jang
Sihyug
S
Murray
Peter J
PJ
Salgame
Padmini
P
Ehrt
Sabine
S
D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D009569:Nitric Oxide / Q000096:biosynthesis; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency* / Q000276:immunology*; D010457:Peptidoglycan / Q000276:immunology; D013154:Spleen / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000172:deficiency; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014774:Virulence
D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide
Blood. 2005 Feb 1;105(3):1195-7
15459013
J Biol Chem. 2003 Mar 14;278(11):8869-72
12527755
Mol Cell Biol. 2003 Nov;23(21):7531-9
14560001
Science. 2005 Feb 4;307(5710):731-4
15692051
Immunity. 2006 Sep;25(3):473-85
16949315
Eur J Cell Biol. 2001 Jan;80(1):31-40
11211933
PLoS Pathog. 2005 Nov;1(3):279-85
16322770
J Immunol Methods. 1999 Feb 1;223(1):77-92
10037236
J Biol Chem. 2003 Feb 21;278(8):5509-12
12514169
Nat Immunol. 2004 Aug;5(8):800-8
15220916
Infect Immun. 1998 Apr;66(4):1277-81
9529042
J Immunol. 2001 Jan 1;166(1):447-57
11123323
Cell Microbiol. 2005 Jan;7(1):53-61
15617523
J Immunol. 2006 Apr 15;176(8):4804-10
16585574
Nat Rev Immunol. 2003 May;3(5):371-82
12766759
Nat Genet. 2001 Sep;29(1):19-20
11528384
J Biol Chem. 2001 Feb 16;276(7):4812-8
11087742
J Immunol. 2004 Sep 1;173(5):3392-7
15322203
Nature. 2001 May 31;411(6837):603-6
11385577
J Biol Chem. 2003 Oct 24;278(43):41702-8
12871942
Microbiol Immunol. 2003;47(5):327-36
12825894
Trends Microbiol. 2005 Mar;13(3):98-102
15737727
J Exp Med. 2003 Oct 6;198(7):987-97
14517275
J Immunol. 2005 Sep 1;175(5):3318-28
16116224
Nature. 2006 Mar 9;440(7081):228-32
16407890
EMBO J. 2004 Apr 7;23(7):1587-97
15044951
Mol Cell Probes. 2007 Apr;21(2):148-51
17113749
Nature. 2002 Mar 14;416(6877):194-9
11894098
Nature. 2001 May 31;411(6837):599-603
11385576
Lancet. 2003 Sep 13;362(9387):887-99
13678977
Clin Infect Dis. 2005 Aug 15;41 Suppl 4:S258-62
16032561
Science. 2001 Feb 23;291(5508):1544-7
11222859
J Exp Med. 2001 Oct 15;194(8):1123-40
11602641
FEMS Immunol Med Microbiol. 2004 Jun 1;41(2):157-60
15145460
J Exp Med. 2005 Dec 19;202(12):1715-24
16365150
Infect Immun. 2000 Dec;68(12):6997-7002
11083824
EMBO Rep. 2001 Aug;2(8):736-42
11463746
Am J Pathol. 2004 Jan;164(1):49-57
14695318
J Immunol. 2002 Oct 1;169(7):3480-4
12244136
Curr Opin Microbiol. 2002 Feb;5(1):76-80
11834373
Science. 1999 Jul 30;285(5428):732-6
10426995