title: Role of TNF in the altered interaction of dormant Mycobacterium tuberculosis with host macrophages.
abstract: Mycobacterium tuberculosis (Mtb) persists within lung granulomas, despite being subjected to diverse stress conditions, including hypoxia. We hypothesized that the response of host phagocytes to Mtb experiencing hypoxia is radically altered and designed in vitro experiment to study this phenomenon. Hypoxia-stressed (Mtb-H) and aerobically grown Mtb (Mtb-A) were used to infect Rhesus Macaque Bone Marrow Derived Macrophages (Rh-BMDMs) and the comparative host response to Mtb infection studied. Mechanistic insights were gained by employing RNAi. Mtb-H accumulated significantly lower bacterial burden during growth in Rh-BMDMs, concomitantly generating a drastically different host transcriptional profile (with only <2% of all genes perturbed by either infection being shared between the two groups). A key component of this signature was significantly higher TNF and apopotosis in Mtb-H- compared to Mtb-A-infected Rh-BMDMs. Silencing of TNF by RNAi reversed the significant control of Mtb replication. These results indicate a potential mechanism for the rapid clearance of hypoxia-conditioned bacilli by phagocytes. In conclusion, hypoxia-conditioned Mtb undergo significantly different interactions with host macrophages compared to Mtb grown in normoxia. These interactions result in the induction of the TNF signaling pathway, activation of apoptosis, and DNA-damage stress response. Our results show that Mtb-H bacilli are particularly susceptible to killing governed by TNF.
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Uma S
authors.initials: US
authors.lastname: Gautam
authors.affiliation: Department of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Smriti
authors.initials: S
authors.lastname: Mehra
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Muhammad H
authors.initials: MH
authors.lastname: Ahsan
authors.affiliation: Department of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, United States of America.
authors.forename: Xavier
authors.initials: X
authors.lastname: Alvarez
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Niu
authors.affiliation: Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Covington, Louisiana, United States of America; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kaushal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015687:Cell Hypoxia / Q000276:immunology; D004249:DNA Damage; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D014409:Tumor Necrosis Factor-alpha
references.citation: J Leukoc Biol. 2010 Jan;87(1):173-83
references.pmid: 19850884
references.citation: J Bacteriol. 1967 Apr;93(4):1374-81
references.pmid: 4962059
references.citation: Curr Biol. 2002 Jul 23;12(14):1263-8
references.pmid: 12176339
references.citation: J Infect Dis. 2013 Apr;207(7):1115-27
references.pmid: 23255564
references.citation: J Biol Chem. 2004 May 28;279(22):23082-7
references.pmid: 15033981
references.citation: Infect Immun. 2008 Jun;76(6):2333-40
references.pmid: 18347040
references.citation: Nucleic Acids Res. 2011 Sep 1;39(17):7400-14
references.pmid: 21653552
references.citation: Annu Rev Microbiol. 2001;55:139-63
references.pmid: 11544352
references.citation: PLoS One. 2012;7(1):e28958
references.pmid: 22235255
references.citation: FEBS Lett. 2004 May 7;565(1-3):75-80
references.pmid: 15135056
references.citation: PLoS One. 2012;7(4):e35847
references.pmid: 22563409
references.citation: J Med Primatol. 2011 Aug;40(4):233-43
references.pmid: 21781131
references.citation: Lancet. 2006 Mar 18;367(9514):938-40
references.pmid: 16546542
references.citation: Nat Rev Microbiol. 2007 Jan;5(1):39-47
references.pmid: 17160001
references.citation: Microbes Infect. 2012 Sep;14(11):959-67
references.pmid: 22546526
references.citation: Mucosal Immunol. 2011 May;4(3):279-87
references.pmid: 21307848
references.citation: J Infect Dis. 2012 Apr 15;205(8):1203-13
references.pmid: 22402035
references.citation: J Biol Chem. 2010 Aug 13;285(33):25500-5
references.pmid: 20558744
references.citation: J Infect Dis. 2013 Apr 15;207(8):1253-61
references.pmid: 23359591
references.citation: J Cell Physiol. 2012 Nov;227(11):3613-20
references.pmid: 22307729
references.citation: PLoS One. 2010 Aug 31;5(8):e12266
references.pmid: 20824205
references.citation: J Invest Dermatol. 2007 Mar;127(3):538-44
references.pmid: 17039240
references.citation: Infect Immun. 1996 Jun;64(6):2062-9
references.pmid: 8675308
references.citation: PLoS One. 2011 Apr 12;6(4):e18648
references.pmid: 21533263
references.citation: Infect Immun. 1993 Oct;61(10):4064-71
references.pmid: 8406793
references.citation: Cell Microbiol. 2010 Mar;12(3):301-9
references.pmid: 20039878
references.citation: J Exp Med. 2005 Jun 6;201(11):1693-7
references.pmid: 15939785
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7534-9
references.pmid: 11416222
references.citation: J Biol Chem. 1996 Aug 16;271(33):20009-17
references.pmid: 8702718
references.citation: Biochem Pharmacol. 2000 Oct 15;60(8):1033-9
references.pmid: 11007939
references.citation: Microbes Infect. 2011 Dec;13(14-15):1242-51
references.pmid: 21813088
references.citation: J Bacteriol. 2014 Feb;196(4):790-9
references.pmid: 24317401
references.citation: J Exp Med. 2003 Sep 1;198(5):693-704
references.pmid: 12953091
references.citation: J Immunol. 2012 Apr 15;188(8):4001-7
references.pmid: 22427634
references.citation: J Immunol. 2006 Mar 15;176(6):3707-16
references.pmid: 16517739
references.citation: Curr Protoc Bioinformatics. 2004 Oct;Chapter 7:Unit 7.9
references.pmid: 18428735
references.citation: J Exp Med. 2003 Sep 1;198(5):705-13
references.pmid: 12953092
references.citation: J Clin Invest. 1995 Feb;95(2):586-92
references.pmid: 7860742
references.citation: J Infect Dis. 2010 Sep 15;202(6):943-53
references.pmid: 20701538
references.citation: J Clin Invest. 1993 May;91(5):2076-83
references.pmid: 7683696
references.citation: PLoS Pathog. 2009 Nov;5(11):e1000659
references.pmid: 19911057
references.citation: J Immunol. 2013 Jul 1;191(1):274-82
references.pmid: 23733870
references.citation: J Infect Dis. 2010 Jun 1;201(11):1743-52
references.pmid: 20394526