Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response.
Inhibition of apoptosis of infected macrophages by pathogenic mycobacteria is suggested to be an important virulence mechanism, but little is known about the mycobacterial proteins involved in the inhibition of apoptosis. In this study we investigated differences in apoptosis and immune response and their correlation with the expression of Mycobacterium tuberculosis complex-specific secretory protein MPT64 in lesions caused by tuberculous or non-tuberculous mycobacteria by analysing the in situ expression of apoptosis-related proteins (FasL, Fas, Bax, Bcl-2), apoptotic cells, inflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, interferon (IFN)-gamma] and MPT64 antigen. The discrimination of mycobacteria was made by nested polymerase chain reaction (PCR) amplification of IS6110, which is specific for M. tuberculosis complex organisms. Forty-seven cases of lymphadenitis with necrotic granulomas were evaluated. With nested PCR, 30/47 cases were positive for M. tuberculosis. MPT64 antigen was detected specifically in the PCR-positive cases. Granulomas caused by tuberculous mycobacteria had fewer apoptotic cells, higher numbers of cells expressing TNF-alpha and TGF-beta and less extensive necrosis than granulomas caused by non-tuberculous mycobacteria. There was a significant negative correlation between apoptotic cells and the number of cells expressing MPT64 antigens, suggesting a role for MPT64 protein in the inhibition of apoptosis. Granulomas with higher amounts of MPT64 also showed a greater number of cells expressing TGF-beta than those with lower amounts of MPT64. In conclusion, this study supports the hypothesis that inhibition of apoptosis is a virulence mechanism for tuberculous mycobacteria. Correlation of MPT64 antigen with expression of macrophage deactivating cytokines and reduced apoptosis suggests its role in pathogenesis and bacillary persistence.
Mustafa
T
T
Section for Microbiology and Immunology, The Gade Institute, University of Bergen, Bergen, Norway. tehmina.mustafa@cih.uib.no
Wiker
H G
HG
Mørkve
O
O
Sviland
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006099:Granuloma / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009161:Mycobacterium / Q000276:immunology; D009164:Mycobacterium Infections / Q000276:immunology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity; D016133:Polymerase Chain Reaction / Q000379:methods; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014388:Tuberculosis, Lymph Node / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014774:Virulence; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000942:Antigens, Bacterial; C494826:BAX protein, human; D001426:Bacterial Proteins; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D018836:Inflammation Mediators; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C060216:MPB70 protein, Mycobacterium bovis
Arch Med Res. 2003 Jan-Feb;34(1):20-5
12604370
Clin Exp Immunol. 1999 Apr;116(1):94-9
10209511
Br J Cancer. 1972 Aug;26(4):239-57
4561027
Infect Immun. 1986 Apr;52(1):293-302
3514457
Cell. 1989 Mar 10;56(5):731-40
2647299
J Immunol. 1989 Jun 15;142(12):4295-300
2542408
Science. 1999 May 28;284(5419):1520-3
10348738
East Afr Med J. 2004 Apr;81(4):171-8
15884281
Immunol Cell Biol. 2005 Dec;83(6):643-50
16266317
Immunology. 2006 Apr;117(4):454-62
16556259
Mod Pathol. 2006 Dec;19(12):1606-14
16980944
Inflammation. 1999 Dec;23(6):507-21
10565565
J Leukoc Biol. 1999 Nov;66(5):763-4
10577507
J Immunol. 2000 Feb 15;164(4):2016-20
10657653
J Pathol. 2000 Aug;191(4):417-25
10918217
Scand J Infect Dis. 2001;33(6):405-7
11450857
Scand J Immunol. 2001 Dec;54(6):630-9
11902340
Scand J Immunol. 2002 Oct;56(4):383-91
12234259
Infect Immun. 1990 Aug;58(8):2675-7
2115027
Infect Immun. 1991 Aug;59(8):2567-72
1906841
Immunol Today. 1991 Jul;12(7):228-33
1822092
J Exp Med. 1993 Dec 1;178(6):2243-7
8245795
J Exp Med. 1994 Oct 1;180(4):1499-509
7931080
J Immunol. 1995 Jan 1;154(1):465-73
7995958
Immunology. 1994 Aug;82(4):591-5
7835922
Scand J Immunol. 1995 Jun;41(6):539-44
7770723
Immunity. 1995 Jun;2(6):561-72
7540941
J Exp Med. 1995 Dec 1;182(6):1777-83
7500022
Am J Respir Cell Mol Biol. 1996 Jul;15(1):64-70
8679223
Infect Immun. 1996 Dec;64(12):5384-9
8945591
J Immunol. 1997 Jan 1;158(1):315-21
8977205
Cell. 1997 Feb 7;88(3):355-65
9039262
Scand J Immunol. 1997 Feb;45(2):115-31
9042423
Immunology. 1997 Apr;90(4):607-17
9176116
J Immunol. 1997 Aug 15;159(4):1594-8
9257817
J Immunol. 1997 Sep 15;159(6):3034-43
9300729
Eur J Immunol. 1997 Sep;27(9):2450-6
9341792
Immunology. 1997 Sep;92(1):1-5
9370916
J Lab Clin Med. 1997 Nov;130(5):469-75
9390634
Infect Immun. 1998 Jul;66(7):3454-6
9632623
Int J Tuberc Lung Dis. 1998 Jul;2(7):541-6
9661819
J Immunol. 1998 Sep 1;161(5):2636-41
9725266
J Infect Dis. 1998 Oct;178(4):1105-14
9806041
J Immunol. 1999 Mar 1;162(5):3031-6
10072555
Am J Respir Cell Mol Biol. 2003 Nov;29(5):545-51
12748057