title: Immunogenicity and protection induced by a Mycobacterium tuberculosis sigE mutant in a BALB/c mouse model of progressive pulmonary tuberculosis.
abstract: Tuberculosis is still one of the main challenges to human global health, leading to about two million deaths every year. One of the reasons for its success is the lack of efficacy of the widely used vaccine Mycobacterium bovis BCG. In this article, we analyze the potential use of an attenuated mutant of Mycobacterium tuberculosis H37Rv lacking the sigma factor sigma(E) as a live vaccine. We have demonstrated that BALB/c mice infected by the intratracheal route with this mutant strain showed significantly higher survival rates and less tissue damage than animals infected with the parental or complemented mutant strain. Although animals infected with the sigE mutant had low bacillary loads, their lungs showed significantly higher production of the protective factors gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), and beta-defensins than those of animals infected with the parental or complemented mutant strain. Moreover, we demonstrate that the sigE mutant, when inoculated subcutaneously, was more attenuated than BCG in immunodeficient nude mice, thus representing a good candidate for a novel attenuated live vaccine strain. Finally, when we used the sigE mutant as a subcutaneous vaccine, it was able to induce a higher level of protection than did BCG with both H37Rv and a highly virulent strain of M. tuberculosis (Beijing code 9501000). Taken together, our findings suggest that the sigE mutant is a very promising strain for the development of a new vaccine against tuberculosis.
authors.affiliation: Experimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubiràn, Mexico City, Mexico.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Hernandez Pando
authors.forename: Leon Diana
authors.initials: LD
authors.lastname: Aguilar
authors.forename: Issar
authors.initials: I
authors.lastname: Smith
authors.forename: Riccardo
authors.initials: R
authors.lastname: Manganelli
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D019001:Nitric Oxide Synthase / Q000032:analysis; D016133:Polymerase Chain Reaction; D012808:Sigma Factor / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D023083:beta-Defensins / Q000032:analysis
chemical_list: D001426:Bacterial Proteins; D012808:Sigma Factor; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; C111259:sigE protein, Bacteria; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase
references.citation: Clin Exp Immunol. 2005 Jul;141(1):21-8
references.pmid: 15958066
references.citation: Eur J Immunol. 2004 Jan;34(1):174-83
references.pmid: 14971043
references.citation: FEMS Microbiol Rev. 2006 Nov;30(6):926-41
references.pmid: 17064287
references.citation: Immunology. 1997 Apr;90(4):607-17
references.pmid: 9176116
references.citation: Vaccine. 2005 Mar 18;23(17-18):2115-20
references.pmid: 15755581
references.citation: Infect Immun. 2003 Dec;71(12):7170-2
references.pmid: 14638810
references.citation: Infect Immun. 2004 Sep;72(9):5511-4
references.pmid: 15322056
references.citation: Clin Exp Immunol. 2003 Jul;133(1):30-7
references.pmid: 12823275
references.citation: Microbiology (Reading). 2009 Apr;155(Pt 4):1093-1102
references.pmid: 19332811
references.citation: JAMA. 1999 Aug 18;282(7):677-86
references.pmid: 10517722
references.citation: Trends Immunol. 2004 Sep;25(9):483-8
references.pmid: 15324741
references.citation: Mol Microbiol. 2006 Apr;60(2):312-30
references.pmid: 16573683
references.citation: J Infect Dis. 2009 Mar 1;199(5):613-8
references.pmid: 19199549
references.citation: J Bacteriol. 2008 Sep;190(17):5963-71
references.pmid: 18606740
references.citation: Mol Microbiol. 1999 Jan;31(2):715-24
references.pmid: 10027986
references.citation: J Infect Dis. 2008 Sep 15;198(6):877-85
references.pmid: 18657035
references.citation: Nat Rev Microbiol. 2004 Jan;2(1):57-65
references.pmid: 15035009
references.citation: N Engl J Med. 1998 Jun 4;338(23):1641-9
references.pmid: 9614254
references.citation: Stain Technol. 1980 Jul;55(4):253-8
references.pmid: 6160651
references.citation: J Bacteriol. 2004 Feb;186(4):895-902
references.pmid: 14761983
references.citation: Science. 1999 May 28;284(5419):1520-3
references.pmid: 10348738
references.citation: Infect Immun. 2004 May;72(5):3038-41
references.pmid: 15102817
references.citation: Nat Med. 2003 May;9(5):503-4
references.pmid: 12692547
references.citation: Immunology. 1996 Sep;89(1):26-33
references.pmid: 8911136
references.citation: J Exp Med. 1993 Dec 1;178(6):2243-7
references.pmid: 8245795
references.citation: Infect Immun. 2002 Dec;70(12):6515-7
references.pmid: 12438319
references.citation: Cytokine. 1998 Nov;10(11):831-40
references.pmid: 10025977
references.citation: Clin Microbiol Rev. 2003 Jul;16(3):463-96
references.pmid: 12857778
references.citation: J Infect Dis. 2006 Sep 1;194(5):697-701
references.pmid: 16897670
references.citation: Vaccine. 2006 Mar 20;24(13):2333-42
references.pmid: 16388878
references.citation: Infect Immun. 2006 Jun;74(6):3296-304
references.pmid: 16714557
references.citation: Lancet. 1995 Nov 18;346(8986):1339-45
references.pmid: 7475776
references.citation: Clin Exp Immunol. 2007 Feb;147(2):330-8
references.pmid: 17223975
references.citation: Tuberculosis (Edinb). 2006 May-Jul;86(3-4):203-10
references.pmid: 16542875
references.citation: Infect Immun. 2006 Mar;74(3):1718-24
references.pmid: 16495544
references.citation: Mol Microbiol. 2001 Jul;41(2):423-37
references.pmid: 11489128
references.citation: Microbes Infect. 2005 Mar;7(3):325-34
references.pmid: 15804490
references.citation: Infect Immun. 1997 Aug;65(8):3317-27
references.pmid: 9234793