title: Persistence of the bacterial pathogen Granulibacter bethesdensis in chronic granulomatous disease monocytes and macrophages lacking a functional NADPH oxidase.
abstract: Granulibacter bethesdensis is a Gram-negative pathogen in patients with chronic granulomatous disease (CGD), a deficiency in the phagocyte NADPH oxidase. Repeated isolation of genetically identical strains from the same patient over years, and prolonged waxing and waning seropositivity in some subjects, raises the possibility of long-term persistence. G. bethesdensis resists killing by serum, CGD polymorphonuclear leukocytes (PMN), and antimicrobial peptides, indicating resistance to nonoxidative killing mechanisms. Although G. bethesdensis extends the survival of PMN, persistent intracellular bacterial survival might rely on longer-lived macrophages and their precursor monocytes. Therefore, we examined phagocytic killing by primary human monocytes and monocyte-derived macrophages (MDM). Cells from both normal and CGD subjects internalized G. bethesdensis similarly. G. bethesdensis stimulated superoxide production in normal monocytes, but to a lesser degree than in normal PMN. Normal but not CGD monocytes and MDM killed G. bethesdensis and required in vitro treatment with IFN-γ to maintain this killing effect. Although in vitro IFN-γ did not enhance G. bethesdensis killing in CGD monocytes, it restricted growth in proportion to CGD PMN residual superoxide production, providing a potential method to identify patients responsive to IFN-γ therapy. In IFN-γ-treated CGD MDM, G. bethesdensis persisted for the duration of the study (7 d) without decreasing viability of the host cells. These results indicate that G. bethesdensis is highly resistant to oxygen-independent microbicides of myeloid cells, requires an intact NADPH oxidase for clearance, and can persist long-term in CGD mononuclear phagocytes, most likely relating to the persistence of this microorganism in infected CGD patients.
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Jessica
authors: J
authors: Chu
authors: Helen H
authors: HH
authors: Song
authors: Kol A
authors: KA
authors: Zarember
authors: Teresa A
authors: TA
authors: Mills
authors: John I
authors: JI
authors: Gallin
mesh_terms: D016947:Acetobacteraceae / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology / Q000276:immunology*; D006105:Granulomatous Disease, Chronic / Q000150:complications* / Q000201:enzymology / Q000382:microbiology; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D018613:Microscopy, Confocal; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D019255:NADPH Oxidases / Q000172:deficiency*
chemical_list: D019255:NADPH Oxidases
references: J Infect. 2008 Sep;57(3):275-7
references: 18558432
references: Infect Dis Clin North Am. 1989 Sep;3(3):461-7
references: 2504811
references: Sci Transl Med. 2011 Oct 12;3(104):104ra102
references: 21998409
references: Infect Immun. 2003 May;71(5):2394-403
references: 12704109
references: PLoS One. 2011 May 02;6(5):e19105
references: 21559306
references: Clin Mol Allergy. 2011 May 31;9(1):10
references: 21624140
references: Infect Immun. 2012 Mar;80(3):975-81
references: 22184421
references: Immunol Cell Biol. 2007 Feb-Mar;85(2):103-11
references: 17213830
references: Can J Anaesth. 2002 Nov;49(9):942-5
references: 12419721
references: Parasite Immunol. 1994 Jul;16(7):371-5
references: 7970876
references: Br Med J. 1957 Nov 9;2(5053):1082-7
references: 13472056
references: J Med Microbiol. 2009 Jul;58(Pt 7):974-976
references: 19502367
references: Infect Immun. 1985 Feb;47(2):502-7
references: 2981774
references: J Clin Microbiol. 2006 Aug;44(8):3048-50
references: 16891542
references: J Clin Invest. 1976 Sep;58(3):705-15
references: 956397
references: APMIS. 1993 Jan;101(1):1-17
references: 8457320
references: N Engl J Med. 2010 Dec 30;363(27):2600-10
references: 21190454
references: PLoS Pathog. 2009 Jul;5(7):e1000534
references: 19649276
references: J Immunol. 2004 Apr 15;172(8):4941-7
references: 15067074
references: J Immunol. 2002 May 1;168(9):4701-10
references: 11971020
references: PLoS One. 2012;7(9):e45781
references: 23049859
references: Annu Rev Immunol. 2008;26:421-52
references: 18303997
references: J Gen Microbiol. 1979 Nov;115(1):69-77
references: 393798
references: Infect Immun. 2011 May;79(5):1984-97
references: 21383054
references: Medicine (Baltimore). 2000 May;79(3):155-69
references: 10844935
references: Infect Immun. 2001 Oct;69(10):6382-90
references: 11553582
references: J Clin Invest. 1989 May;83(5):1457-65
references: 2496141
references: J Clin Invest. 1987 Oct;80(4):1009-16
references: 2821069
references: J Immunol. 1988 Jun 1;140(11):3978-81
references: 3131422
references: Am J Kidney Dis. 2004 Aug;44(2):e15-7
references: 15264206
references: J Med Microbiol. 2010 Jul;59(Pt 7):848-852
references: 20339020
references: J Clin Microbiol. 1985 Nov;22(5):863-4
references: 4056012
references: Emerg Infect Dis. 2007 May;13(5):784-5
references: 18044042
references: J Leukoc Biol. 2003 May;73(5):591-9
references: 12714573
references: Infect Immun. 2012 Mar;80(3):996-1006
references: 22215736
references: J Leukoc Biol. 1989 Nov;46(5):434-40
references: 2509611
references: Semin Pediatr Infect Dis. 2002 Oct;13(4):263-72
references: 12491232
references: J Exp Med. 1987 Nov 1;166(5):1377-89
references: 3316470
references: J Clin Microbiol. 2009 Jul;47(7):2084-9
references: 19420176
references: Infect Immun. 1995 Aug;63(8):3054-61
references: 7622230
references: Infect Immun. 1994 Aug;62(8):3197-205
references: 8039889
references: Vet Microbiol. 1999 Aug 31;68(3-4):235-44
references: 10510042
references: Vet Microbiol. 2002 Dec 20;90(1-4):383-94
references: 12414158
references: J Immunol. 2010 Oct 1;185(7):4030-41
references: 20805415
references: Eur J Immunol. 2001 Mar;31(3):929-38
references: 11241298
references: Int J Hypertens. 2010 Aug 17;2010:646929
references: 20981357
references: Am J Respir Cell Mol Biol. 2008 Apr;38(4):380-5
references: 18192503
references: J Clin Invest. 1989 Mar;83(3):865-75
references: 2921324
references: Emerg Infect Dis. 2010 Sep;16(9):1341-8
references: 20735916
references: Nat Cell Biol. 2002 Dec;4(12):945-54
references: 12447391
references: Infect Immun. 2003 Mar;71(3):1481-90
references: 12595466
references: PLoS Pathog. 2006 Apr;2(4):e28
references: 16617373
references: J Interferon Cytokine Res. 2007 May;27(5):353-64
references: 17523867
references: Infect Immun. 2001 Jul;69(7):4276-86
references: 11401964
references: Blood. 1966 Sep;28(3):455-64
references: 5918472
references: J Clin Microbiol. 2010 Nov;48(11):3935-42
references: 20826638
references: Curr Opin Immunol. 2001 Aug;13(4):417-28
references: 11498297
references: J Bacteriol. 1998 Oct;180(20):5369-74
references: 9765568
references: Emerg Infect Dis. 2008 Jun;14(6):997-8
references: 18507930
references: Eur J Immunol. 2007 Apr;37(4):1087-96
references: 17330823
references: Nat Med. 2007 Mar;13(3):290-4
references: 17342142
references: J Clin Invest. 1978 Feb;61(2):480-8
references: 202614
references: Pediatr Pulmonol. 2003 May;35(5):392-9
references: 12687597
references: Infect Immun. 2003 Apr;71(4):2110-9
references: 12654833
references: J Bacteriol. 1975 Apr;122(1):139-44
references: 235507
references: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5121-6
references: 17360363
references: Front Microbiol. 2012 Jan 11;2:281
references: 22275911
references: J Immunol. 2007 May 15;178(10):6367-73
references: 17475866
references: Nat Rev Immunol. 2004 Mar;4(3):181-9
references: 15039755
references: Cell. 1984 Jan;36(1):27-33
references: 6692469
references: Clin Exp Immunol. 2011 Jun;164(3):346-56
references: 21413941
references: Ann Intern Med. 1979 Apr;90(4):522-6
references: 373542
references: J Immunol. 2012 Jun 1;188(11):5752-65
references: 22547697
references: Immunology. 2009 Oct;128(2):253-9
references: 19740382
references: Proc Natl Acad Sci U S A. 1988 Jul;85(13):4874-8
references: 2838849
references: J Immunol. 2000 Jun 1;164(11):5998-6004
references: 10820283
references: Clin Exp Immunol. 1990 Aug;81(2):339-45
references: 2117512
references: Int J Med Microbiol. 2001 Nov;291(5):331-43
references: 11727817
references: PLoS Pathog. 2007 Jul;3(7):e110
references: 17658950