Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections.
Pulmonary infections with nontuberculous mycobacteria (P-NTM), such as by Mycobacterium avium complex (M. avium), are increasingly found in the elderly, but the underlying mechanisms are unclear. Recent studies suggest that adaptive immunity is necessary, but not sufficient, for host defense against mycobacteria. Heme oxygenase-1 (HO-1) has been recognized as a critical modulator of granuloma formation and programmed cell death in mycobacterial infections. Old mice (18-21 mo) infected with M. avium had attenuated HO-1 response with diffuse inflammation, high burden of mycobacteria, poor granuloma formation, and decreased survival (45%), while young mice (4-6 mo) showed tight, well-defined granuloma, increased HO-1 expression, and increased survival (95%). To further test the role of HO-1 in increased susceptibility to P-NTM infections in the elderly, we used old and young HO-1+/+and HO-1-/-mice. The transcriptional modulation of the JAK/STAT signaling pathway in HO-1-/-mice due to M. avium infection demonstrated similarities to infected wild-type old mice with upregulation of SOCS3 and inhibition of Bcl2. Higher expression of SOCS3 with downregulation of Bcl2 resulted in higher macrophage death via cellular necrosis. Finally, peripheral blood monocytes (PBMCs) from elderly patients with P-NTM also demonstrated attenuated HO-1 responses after M. avium stimulation and increased cell death due to cellular necrosis (9.69% ± 2.02) compared with apoptosis (4.75% ± 0.98). The augmented risk for P-NTM in the elderly is due, in part, to attenuated HO-1 responses, subsequent upregulation of SOCS3, and inhibition of Bcl2, leading to programmed cell death of macrophages, and sustained infection.
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Ranu
0000-0001-5389-3584
R
Surolia
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Suman
S
Karki
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Zheng
Z
Wang
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Tejaswini
T
Kulkarni
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Fu Jun
FJ
Li
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Shikhar
S
Vohra
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Hitesh
H
Batra
Department of Medicine, National Jewish Health, University of Colorado, Denver, Colorado.
Jerry A
JA
Nick
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Steven R
SR
Duncan
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama.
Victor J
VJ
Thannickal
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama.|KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa; and.
Adrie J C
AJ
Steyn
Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama.|Birmingham VA Medical Center, University of Alabama at Birmingham, Birmingham, Alabama.
Anupam
A
Agarwal
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, Alabama; vantony@uabmc.edu.
Veena B
VB
Antony
D000368:Aged; D000375:Aging / Q000473:pathology; D000818:Animals; D016923:Cell Death; D004198:Disease Susceptibility; D015971:Gene Expression Regulation, Enzymologic; D006099:Granuloma / Q000382:microbiology / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000382:microbiology / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D009165:Mycobacterium Infections, Nontuberculous / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009162:Mycobacterium avium / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000201:enzymology* / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D014158:Transcription, Genetic
D019253:Proto-Oncogene Proteins c-bcl-2; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D051547:Heme Oxygenase-1
SOCS3; aging; cell death; heme oxygenase 1; nontuberculosis mycobacterium
J Exp Med. 1994 Oct 1;180(4):1499-509
7931080
J Biol Chem. 2005 Dec 23;280(51):41827-34
16246838
Invest Ophthalmol Vis Sci. 2004 May;45(5):1562-5
15111615
Infect Immun. 1993 Jul;61(7):3093-7
8514420
Am J Respir Crit Care Med. 2010 Oct 1;182(7):970-6
20538958
J Gerontol A Biol Sci Med Sci. 2006 Feb;61(2):125-35
16510856
J Immunol. 2006 Nov 1;177(9):6052-61
17056531
J Infect Dis. 2000 Apr;181(4):1506-9
10762586
Dent J. 1978 Jan;44(1):26-7
272989
Cell. 2009 Jan 9;136(1):37-49
19135887
J Infect Dis. 2002 Nov 1;186(9):1277-82
12402197
J Immunol. 2007 Mar 15;178(6):3777-85
17339476
Immun Ageing. 2013 Jun 08;10(1):22
23758797
Endocrinology. 2000 Jun;141(6):2003-10
10830283
Vet Med Int. 2011;2011:712369
21776352
Clin Chest Med. 2007 Dec;28(4):773-81, vi
17967293
Leukemia. 1997 Apr;11 Suppl 3:380-2
9209397
J Clin Microbiol. 1979 Feb;9(2):194-6
429541
J Immunol. 1993 Nov 15;151(10):5425-30
8228235
Immunol Cell Biol. 2000 Aug;78(4):334-41
10947857
PLoS One. 2012;7(10):e47573
23118880
Lab Invest. 2012 Nov;92 (11):1541-52
22964851
N Engl J Med. 1989 Sep 28;321(13):863-8
2770822
EMBO J. 2000 Jul 3;19(13):3325-36
10880445
Am J Physiol Lung Cell Mol Physiol. 2015 Aug 1;309(3):L280-92
26071551
Tuberculosis (Edinb). 2011 Nov;91(6):497-509
21733755
Mol Endocrinol. 1998 Jul;12 (7):954-61
9658400
FASEB J. 2006 Oct;20(12 ):2156-8
16971418
Clin Microbiol Rev. 2002 Apr;15(2):294-309
11932234
Immunity. 1997 Sep;7(3):433-44
9324363
Immunology. 2015 Feb;144(2):321-32
25179131
PLoS Pathog. 2013 Feb;9(2):e1003190
23436998
J Gerontol A Biol Sci Med Sci. 1998 Jan;53(1):M20-6
9467429
Blood. 2005 Mar 15;105(6):2294-9
15572589
Free Radic Biol Med. 2009 Jul 1;47(1):1-12
19362144
J Gerontol A Biol Sci Med Sci. 2006 Nov;61(11):1111-8
17167151
Biogerontology. 2009 Apr;10 (2):173-80
18690550
Immunobiology. 2015 Aug;220(8):947-53
25720636
PLoS One. 2014 Mar 14;9(3):e91879
24632814
Arch Biochem Biophys. 2014 Feb 15;544:87-95
24161941
J Immunol. 2006 Dec 1;177(11):7880-8
17114459
Nat Med. 2002 Mar;8(3):240-6
11875494
J Immunol. 2015 Sep 15;195(6):2763-73
26268658
Clin Infect Dis. 2001 Oct 1;33(7):1034-9
11528577
FASEB J. 1999 Mar;13(3):485-94
10064615
J Immunol. 2000 Nov 1;165(9):5227-37
11046056
PLoS One. 2012;7(3):e34280
22479586
Bioinformatics. 2003 Jan 22;19(2):295-6
12538257
Nat Rev Immunol. 2012 Apr 20;12(5):352-66
22517424
J Gerontol A Biol Sci Med Sci. 2009 Apr;64(4):419-25
19196643
Mol Biol Rep. 2012 Sep;39(9):8853-60
22714916
J Leukoc Biol. 2006 Nov;80(5):1136-44
16943387
Nat Immunol. 2003 Jun;4(6):507-9
12774070
Infect Immun. 2013 Jul;81(7):2536-45
23630967
Am J Respir Crit Care Med. 2008 Nov 15;178(10):999-1000
18987345
Am J Respir Crit Care Med. 2013 Jan 15;187(2):197-205
23144328
Biochem J. 2004 May 1;379(Pt 3):823-32
14748742
FASEB J. 2014 Mar;28(3):1122-31
24265486