title: The ΔfbpA attenuated candidate vaccine from Mycobacterium tuberculosis, H37Rv primes for a stronger T-bet dependent Th1 immunity in mice.
abstract: The ΔfbpA candidate vaccine derived from Mycobacterium tuberculosis (H37Rv) (Mtb) protects mice better than BCG against tuberculosis, and we investigated the hypothesis that ΔfbpA may induce a stronger Th1 immunity. Since T-bet transcription factor regulates Th1 immunity, mice infected with ΔfbpA, BCG vaccine and related mycobacteria were analyzed for T-bet positive T cells. Mouse dendritic cells (DCs) or macrophages were also pulsed with excretory-secreted antigens (ES; Antigen-85B, ESAT-6 and CFP10) and cocultured with T cells from immunized or naïve mice and tested for in vitro induction of T-bet and IFN-γ. In both models, ΔfbpA mutant induced a stronger response of T-bet(+)CD4 T cells, which correlated with an increased expansion of IFN-γ(+)CD4 T cells in vivo and in vitro. When DCs pulsed with ES antigens were allowed to stimulate T cells, ESAT-6 and CFP-10 failed to induce a recall expansion of T-bet(+)IFN-γ(+)CD4 T cells from BCG vaccinated mice. Thus, deletion of RD1 in BCG seems to reduce its ability to induce T-bet and induce stronger Th1 immunity. Finally, mice were vaccinated with ΔfbpA and BCG and challenged with virulent Mtb for evaluation of protection and T cell expansion. ΔfbpA vaccinated mice showed a rapid and stronger expansion of CD4(+)CXCR3(+) IFN-γ(+) T cells in the lungs of Mtb challenged mice, compared to those which had BCG vaccine. ΔfbpA immunized mice also showed a better decline of the Mtb bacterial counts of the lungs. Mtb derived ΔfbpA candidate vaccine therefore induces qualitatively better T-bet dependent Th1 immunity than BCG vaccine.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, 6431 Fannin, MSB 2.200, Houston, TX, USA.
authors.forename: Cherie M
authors.initials: CM
authors.lastname: Roche
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.forename: Devin R
authors.initials: DR
authors.lastname: Lindsey
authors.forename: Akshay
authors.initials: A
authors.lastname: Meher
authors.forename: Kimberly
authors.initials: K
authors.lastname: Schluns
authors.forename: Ashish
authors.initials: A
authors.lastname: Arora
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Armitige
authors.forename: Chinnaswamy
authors.initials: C
authors.lastname: Jagannath
mesh_terms: D000217:Acyltransferases / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D015169:Colony Count, Microbial; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology; D004195:Disease Models, Animal; D006867:Hydrolases / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; D006867:Hydrolases; C527647:HsaD protein, Mycobacterium tuberculosis
references.citation: J Leukoc Biol. 2007 Oct;82(4):956-67
references.pmid: 17675563
references.citation: Scand J Immunol. 1999 Aug;50(2):137-44
references.pmid: 10447917
references.citation: J Leukoc Biol. 2007 Jan;81(1):212-20
references.pmid: 16997854
references.citation: J Immunol. 2006 Mar 1;176(5):3019-27
references.pmid: 16493060
references.citation: Microbes Infect. 2005 May;7(5-6):905-10
references.pmid: 15878834
references.citation: Nat Med. 2009 Mar;15(3):267-76
references.pmid: 19252503
references.citation: J Leukoc Biol. 2004 May;75(5):721-30
references.pmid: 14726500
references.citation: Semin Immunol. 2004 Apr;16(2):107-17
references.pmid: 15036234
references.citation: Infect Dis Clin North Am. 1999 Mar;13(1):169-85, vii-viii
references.pmid: 10198798
references.citation: Microbes Infect. 2006 Apr;8(5):1339-46
references.pmid: 16697232
references.citation: Vet Microbiol. 2006 Feb 25;112(2-4):163-9
references.pmid: 16325357
references.citation: Eur J Immunol. 2006 Dec;36(12):3346-55
references.pmid: 17109467
references.citation: J Allergy Clin Immunol. 2004 May;113(5):987-94
references.pmid: 15131585
references.citation: Nat Rev Mol Cell Biol. 2001 Aug;2(8):569-77
references.pmid: 11483990
references.citation: Pathol Biol (Paris). 2005 Feb;53(1):35-40
references.pmid: 15620608
references.citation: Electrophoresis. 2000 Oct;21(16):3378-85
references.pmid: 11079558
references.citation: Am J Clin Pathol. 2003 Dec;120(6):866-73
references.pmid: 14671975
references.citation: Indian J Pediatr. 2000 Feb;67(2 Suppl):S58-62
references.pmid: 11129910
references.citation: J Exp Med. 2003 Jan 6;197(1):7-17
references.pmid: 12515809
references.citation: Infect Immun. 2000 Feb;68(2):767-78
references.pmid: 10639445
references.citation: Clin Microbiol Rev. 2005 Oct;18(4):687-702
references.pmid: 16223953
references.citation: Infect Immun. 2004 Dec;72(12):7084-95
references.pmid: 15557632
references.citation: Springer Semin Immunopathol. 2005 Jan;26(3):289-307
references.pmid: 15609003
references.citation: FEBS J. 2006 Apr;273(7):1445-62
references.pmid: 16689931
references.citation: Cell Immunol. 2000 Apr 10;201(1):63-74
references.pmid: 10805975
references.citation: J Leukoc Biol. 2005 Jul;78(1):106-13
references.pmid: 15845642
references.citation: Trends Cell Biol. 1995 Mar;5(3):125-8
references.pmid: 14732168
references.citation: Tuberculosis (Edinb). 2006 May-Jul;86(3-4):163-8
references.pmid: 16678489
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5299-304
references.pmid: 9560270
references.citation: J Immunol. 1998 Nov 1;161(9):4882-93
references.pmid: 9794422
references.citation: J Biol Regul Homeost Agents. 2000 Jul-Sep;14(3):218-9
references.pmid: 11037056
references.citation: Immunology. 1996 Sep;89(1):26-33
references.pmid: 8911136
references.citation: Immunol Res. 2004;29(1-3):187-96
references.pmid: 15181281
references.citation: J Immunol. 2003 May 1;170(9):4457-64
references.pmid: 12707321
references.citation: J Immunol. 2005 Mar 15;174(6):3570-9
references.pmid: 15749894
references.citation: APMIS. 2003 Jul-Aug;111(7-8):675-97
references.pmid: 12974772
references.citation: J Leukoc Biol. 2004 Oct;76(4):827-34
references.pmid: 15240755
references.citation: Nat Rev Microbiol. 2005 Aug;3(8):656-62
references.pmid: 16012514
references.citation: Proc Am Thorac Soc. 2005;2(5):412-6
references.pmid: 16322591
references.citation: Ann Rheum Dis. 2002 Nov;61 Suppl 2:ii54-8
references.pmid: 12379623
references.citation: Blood. 2005 Nov 15;106(10):3432-9
references.pmid: 16014561
references.citation: Cell. 2000 Mar 17;100(6):655-69
references.pmid: 10761931
references.citation: Science. 2005 Jan 21;307(5708):430-3
references.pmid: 15662016
references.citation: Tuberculosis (Edinb). 2004;84(1-2):93-101
references.pmid: 14670350