title: Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV- and HIV+ subjects.
abstract: Hematogenous dissemination of Mycobacterium tuberculosis (M. tb) occurs during both primary and reactivated tuberculosis (TB). Although hematogenous dissemination occurs in non-HIV TB patients, in ∼80% of these patients, TB manifests exclusively as pulmonary disease. In contrast, extrapulmonary, disseminated, and/or miliary TB is seen in 60-70% of HIV-infected TB patients, suggesting that hematogenous dissemination is likely more common in HIV+ patients. To understand M. tb adaptation to the blood environment during bacteremia, we have studied the transcriptome of M. tb replicating in human whole blood. To investigate if M. tb discriminates between the hematogenous environments of immunocompetent and immunodeficient individuals, we compared the M. tb transcriptional profiles during replication in blood from HIV- and HIV+ donors. Our results demonstrate that M. tb survives and replicates in blood from both HIV- and HIV+ donors and enhances its virulence/pathogenic potential in the hematogenous environment. The M. tb blood-specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, potential evasion of immune surveillance, and enhanced expression of important virulence factors that drive active M. tb infection and dissemination. These changes are accentuated during bacterial replication in blood from HIV+ patients. Furthermore, the expression of ESAT-6, which participates in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood, especially during growth in blood from HIV+ patients. Preliminary experiments also demonstrate that ESAT-6 promotes HIV replication in U1 cells. These studies provide evidence, for the first time, that during bacteremia, M. tb can adapt to the blood environment by modifying its transcriptome in a manner indicative of an enhanced-virulence phenotype that favors active infection. Additionally, transcriptional modifications in HIV+ blood may further accentuate M. tb virulence and drive both M. tb and HIV infection.
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Ryndak
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Veterans Affairs New York Harbor Healthcare System, New York, New York, United States of America; Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Hualin
authors.initials: H
authors.lastname: Li
authors.affiliation: Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Meng
authors.affiliation: Veterans Affairs New York Harbor Healthcare System, New York, New York, United States of America; Department of Pathology, New York University Langone Medical Center, New York, New York, United States of America.
authors.forename: Suman
authors.initials: S
authors.lastname: Laal
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D058947:Bacterial Secretion Systems / Q000235:genetics; D002473:Cell Wall / Q000378:metabolism; D020869:Gene Expression Profiling; D018506:Gene Expression Regulation, Plant; D005798:Genes, Bacterial; D016655:HIV Core Protein p24 / Q000378:metabolism; D006679:HIV Seropositivity / Q000097:blood* / Q000235:genetics / Q000382:microbiology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000254:growth & development*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D013312:Stress, Physiological / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D014779:Virus Replication
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D016655:HIV Core Protein p24; D011994:Recombinant Proteins; D007501:Iron
references.citation: Rev Infect Dis. 1991 Nov-Dec;13(6):1089-92
references.pmid: 1775842
references.citation: Infect Immun. 2008 Feb;76(2):717-25
references.pmid: 18070897
references.citation: J Immunol. 1996 Aug 1;157(3):1271-8
references.pmid: 8757635
references.citation: Lung. 2013 Feb;191(1):27-34
references.pmid: 23180033
references.citation: J Infect Dis. 2003 Jan 1;187(1):117-23
references.pmid: 12508154
references.citation: Am Rev Respir Dis. 1989 Dec;140(6):1611-3
references.pmid: 2513763
references.citation: Infect Immun. 2002 Jul;70(7):3371-81
references.pmid: 12065475
references.citation: Mol Microbiol. 2001 Jan;39(1):1-11
references.pmid: 11123683
references.citation: J Vis Exp. 2011 Sep 14;(55):
references.pmid: 21946922
references.citation: Infect Immun. 2006 Feb;74(2):1233-42
references.pmid: 16428773
references.citation: Infect Immun. 1997 Nov;65(11):4515-24
references.pmid: 9353028
references.citation: Mol Microbiol. 2010 Jan;75(1):92-106
references.pmid: 19906174
references.citation: Infect Immun. 2007 Apr;75(4):1870-7
references.pmid: 17283104
references.citation: PLoS One. 2012;7(4):e35847
references.pmid: 22563409
references.citation: Int J Tuberc Lung Dis. 2001 Aug;5(8):763-8
references.pmid: 11495268
references.citation: Arch Biochem Biophys. 2004 Mar 1;423(1):182-91
references.pmid: 14871480
references.citation: J Infect Dis. 1992 Jan;165(1):87-92
references.pmid: 1727901
references.citation: J Infect Dis. 2000 Sep;182(3):895-901
references.pmid: 10950786
references.citation: Southeast Asian J Trop Med Public Health. 2011 Jul;42(4):876-89
references.pmid: 22299470
references.citation: Infect Immun. 1998 Feb;66(2):794-9
references.pmid: 9453643
references.citation: APMIS. 2002 Sep;110(9):625-9
references.pmid: 12529015
references.citation: Tuberculosis (Edinb). 2008 Jul;88(4):295-306
references.pmid: 18321783
references.citation: Expert Rev Mol Med. 2011 Dec 16;13:e39
references.pmid: 22172201
references.citation: Clin Microbiol Infect. 2010 Jun;16(6):627-30
references.pmid: 19709128
references.citation: Nucleic Acids Res. 2005 Feb 17;33(3):e29
references.pmid: 15718295
references.citation: Mol Microbiol. 2002 Feb;43(3):717-31
references.pmid: 11929527
references.citation: J Exp Med. 1993 May 1;177(5):1511-6
references.pmid: 8478621
references.citation: Mol Cell Proteomics. 2006 Nov;5(11):2102-13
references.pmid: 16899542
references.citation: Arch Intern Med. 1993 Feb 22;153(4):496-500
references.pmid: 8435029
references.citation: Am J Epidemiol. 2007 May 15;165(10):1134-42
references.pmid: 17339383
references.citation: Clin Diagn Lab Immunol. 2002 Jul;9(4):901-7
references.pmid: 12093693
references.citation: Medicine (Baltimore). 1991 Nov;70(6):384-97
references.pmid: 1956280
references.citation: Braz J Infect Dis. 2013 Jan-Feb;17(1):110-1
references.pmid: 23290474
references.citation: Microbes Infect. 2010 Oct;12(11):828-37
references.pmid: 20685396
references.citation: PLoS One. 2010 Oct 26;5(10):e13356
references.pmid: 21048946
references.citation: Tuberculosis (Edinb). 2003;83(1-3):131-4
references.pmid: 12758202
references.citation: Clin Infect Dis. 1997 Oct;25(4):888-95
references.pmid: 9356804
references.citation: Nature. 2004 Sep 2;431(7004):84-7
references.pmid: 15343336
references.citation: Nature. 1996 Jun 13;381(6583):571-9
references.pmid: 8637592
references.citation: Immunotherapy. 2012 Jun;4(6):629-47
references.pmid: 22788130
references.citation: Am J Pathol. 2005 Feb;166(2):455-65
references.pmid: 15681829
references.citation: Am Fam Physician. 2005 Nov 1;72(9):1761-8
references.pmid: 16300038
references.citation: Curr Mol Med. 2007 May;7(3):287-96
references.pmid: 17504113
references.citation: PLoS One. 2012;7(3):e34156
references.pmid: 22479548
references.citation: Adv Exp Med Biol. 2013;783:199-223
references.pmid: 23468111
references.citation: Cell Host Microbe. 2007 Nov 15;2(5):352-64
references.pmid: 18005756
references.citation: Clin Dev Immunol. 2011;2011:497203
references.pmid: 21318182
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11342-7
references.pmid: 22733768
references.citation: Proc Natl Acad Sci U S A. 1989 Mar;86(5):1624-8
references.pmid: 2922401
references.citation: J Infect Dis. 2001 Apr 15;183(8):1300-3
references.pmid: 11262217
references.citation: Int J Tuberc Lung Dis. 2001 Mar;5(3):225-32
references.pmid: 11326821
references.citation: Clin Infect Dis. 2004 Jan 15;38(2):199-205
references.pmid: 14699451
references.citation: Nat Med. 2008 Aug;14(8):849-54
references.pmid: 18641659
references.citation: J Formos Med Assoc. 2007 May;106(5):355-64
references.pmid: 17561470
references.citation: Science. 1988 Apr 29;240(4852):640-2
references.pmid: 2834821
references.citation: Virulence. 2012 Nov 15;3(7):654-9
references.pmid: 23154283
references.citation: Tuberculosis (Edinb). 2004;84(3-4):218-27
references.pmid: 15207491
references.citation: J Infect Dis. 2005 Jul 1;192(1):98-106
references.pmid: 15942899
references.citation: Nature. 2009 Jun 18;459(7249):950-6
references.pmid: 19448609
references.citation: PLoS One. 2008 Sep 04;3(9):e3143
references.pmid: 18769548
references.citation: Mol Microbiol. 2012 Mar;83(6):1195-209
references.pmid: 22340629
references.citation: Trop Med Int Health. 2004 Aug;9(8):928-34
references.pmid: 15304000
references.citation: Philos Trans R Soc Lond B Biol Sci. 1993 Mar 29;339(1289):363-7; discussion 367-8
references.pmid: 7684139
references.citation: PLoS One. 2010 Mar 10;5(3):e9611
references.pmid: 20224771
references.citation: Int J Tuberc Lung Dis. 2007 Jun;11(6):624-31
references.pmid: 17519093
references.citation: Infect Immun. 2011 Apr;79(4):1407-17
references.pmid: 21245275
references.citation: J Biol Chem. 2005 Jun 3;280(22):20961-7
references.pmid: 15809303
references.citation: Adv Microb Physiol. 2012;60:263-324
references.pmid: 22633061
references.citation: Clin Vaccine Immunol. 2013 May;20(5):704-11
references.pmid: 23486418
references.citation: J Infect Dis. 2012 Oct;206(8):1194-205
references.pmid: 22732919
references.citation: J Bacteriol. 2011 Apr;193(7):1767-70
references.pmid: 21296960
references.citation: Mol Microbiol. 2009 Aug;73(3):329-40
references.pmid: 19602152
references.citation: Clin Vaccine Immunol. 2009 Jan;16(1):49-54
references.pmid: 19005024
references.citation: Nat Med. 2001 Jun;7(6):732-7
references.pmid: 11385512
references.citation: PLoS Pathog. 2011 May;7(5):e1002027
references.pmid: 21589640
references.citation: J Bacteriol. 2003 Dec;185(24):7247-56
references.pmid: 14645286
references.citation: Science. 2002 Feb 8;295(5557):1073-7
references.pmid: 11799204
references.citation: J Bacteriol. 2002 Jul;184(14):4025-32
references.pmid: 12081975
references.citation: Trends Microbiol. 2002 May;10(5):209-12
references.pmid: 11973144
references.citation: PLoS Pathog. 2010 Mar 05;6(3):e1000794
references.pmid: 20221442
references.citation: Mol Microbiol. 2008 Feb;67(3):672-84
references.pmid: 18186793
references.citation: J Exp Med. 1996 Apr 1;183(4):1527-32
references.pmid: 8666910
references.citation: Nature. 2000 Sep 14;407(6801):211-5
references.pmid: 11001062
references.citation: Mol Microbiol. 2006 May;60(4):999-1013
references.pmid: 16677310
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7534-9
references.pmid: 11416222
references.citation: Arch Biochem Biophys. 2009 Jan 1;481(1):1-15
references.pmid: 18977196
references.citation: Mol Cell Proteomics. 2003 Dec;2(12):1284-96
references.pmid: 14532352
references.citation: PLoS Comput Biol. 2012;8(9):e1002688
references.pmid: 23028286
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4602-7
references.pmid: 15070764
references.citation: Medicine (Baltimore). 1990 Nov;69(6):375-83
references.pmid: 2122171
references.citation: Arch Intern Med. 1995 Jul 24;155(14):1537-42
references.pmid: 7605156
references.citation: J Virol. 2000 Aug;74(15):7096-107
references.pmid: 10888650
references.citation: Int J Tuberc Lung Dis. 2002 Dec;6(12):1067-74
references.pmid: 12546114
references.citation: Microbes Infect. 2008 Jul;10(9):995-1004
references.pmid: 18762264
references.citation: Infect Immun. 2003 Nov;71(11):6338-43
references.pmid: 14573653
references.citation: Infect Immun. 2002 Jun;70(6):2787-95
references.pmid: 12010964
references.citation: Lancet. 1993 Jul 17;342(8864):143-6
references.pmid: 8101257
references.citation: Infect Immun. 2008 Dec;76(12):5478-87
references.pmid: 18852239
references.citation: Respirology. 2007 Mar;12(2):311
references.pmid: 17298472
references.citation: J Exp Med. 2003 Sep 1;198(5):693-704
references.pmid: 12953091
references.citation: J Bacteriol. 2012 Feb;194(3):567-75
references.pmid: 22101841
references.citation: Prog Lipid Res. 2005 Sep;44(5):259-302
references.pmid: 16115688
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12420-5
references.pmid: 14557547
references.citation: Microb Pathog. 2010 Dec;49(6):311-4
references.pmid: 20638467
references.citation: Infect Immun. 2008 Jun;76(6):2333-40
references.pmid: 18347040
references.citation: Tuberculosis (Edinb). 2003;83(1-3):91-7
references.pmid: 12758196
references.citation: Tuber Lung Dis. 1998;79(2):127-32
references.pmid: 10645451
references.citation: Infect Immun. 1991 Jun;59(6):1905-10
references.pmid: 1903768
references.citation: J Virol. 1998 Nov;72(11):9384-91
references.pmid: 9765494
references.citation: J Biol Chem. 2002 Oct 11;277(41):38148-58
references.pmid: 12138124
references.citation: Microbes Infect. 1999 May;1(6):429-35
references.pmid: 10602675
references.citation: Biochemistry. 2012 Feb 21;51(7):1518-31
references.pmid: 22283334
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: Clin Dev Immunol. 2011;2011:587315
references.pmid: 21253470
references.citation: J Acquir Immune Defic Syndr (1988). 1994 Jul;7(7):727-33
references.pmid: 8207650
references.citation: Br J Nutr. 2003 Sep;90(3):541-50
references.pmid: 13129459
references.citation: J Exp Med. 2003 Sep 1;198(5):705-13
references.pmid: 12953092
references.citation: Am J Respir Crit Care Med. 1997 Mar;155(3):996-1003
references.pmid: 9117038
references.citation: Mol Microbiol. 2002 Nov;46(3):709-17
references.pmid: 12410828
references.citation: PLoS One. 2013 Aug 05;8(8):e70305
references.pmid: 23940557
references.citation: Infect Immun. 2001 Oct;69(10):5967-73
references.pmid: 11553532
references.citation: Eur J Clin Microbiol Infect Dis. 2008 Jun;27(6):423-31
references.pmid: 18189149
references.citation: Res Microbiol. 2006 Jun;157(5):445-55
references.pmid: 16483748
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12706-11
references.pmid: 11675502
references.citation: Biochimie. 2012 Jan;94(1):110-6
references.pmid: 22005451
references.citation: J Pediatr Hematol Oncol. 2012 Jan;34(1):13-6
references.pmid: 22215095
references.citation: Mol Microbiol. 1999 Jan;31(1):1-8
references.pmid: 9987104
references.citation: Mol Microbiol. 2004 Jan;51(2):359-70
references.pmid: 14756778
references.citation: J Immunol. 2013 Jul 1;191(1):274-82
references.pmid: 23733870
references.citation: AIDS. 2005 Jul 22;19(11):1113-24
references.pmid: 15990564
references.citation: J Infect Dis. 1978 Aug;138(2):237-41
references.pmid: 98601
references.citation: Clin Diagn Lab Immunol. 1997 Jan;4(1):49-56
references.pmid: 9008280
references.citation: J Bacteriol. 2010 Mar;192(6):1662-70
references.pmid: 20023019
references.citation: Infect Immun. 2012 Sep;80(9):3018-33
references.pmid: 22689819
references.citation: Semin Immunopathol. 2013 Jul;35(4):377-94
references.pmid: 23553214
references.citation: PLoS Med. 2008 Apr 1;5(4):e75
references.pmid: 18384229
references.citation: Cell Microbiol. 2007 Jun;9(6):1376-84
references.pmid: 17466013
references.citation: Clin Infect Dis. 2010 Jun 1;50(11):1524-31
references.pmid: 20415570
references.citation: J Korean Med Sci. 2006 Dec;21(6):1028-32
references.pmid: 17179681
references.citation: BMC Genomics. 2008 Feb 25;9:94
references.pmid: 18298834
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5051-6
references.pmid: 21383189