title: Impact of Mycobacterium tuberculosis RD1-locus on human primary dendritic cell immune functions.
abstract: Modern strategies to develop vaccines against Mycobacterium tuberculosis (Mtb) aim to improve the current Bacillus Calmette-Guerin (BCG) vaccine or to attenuate the virulence of Mtb vaccine candidates. In the present study, the impact of wild type or mutated region of difference 1 (RD1) variants on the immunogenicity of Mtb and BCG recombinants was investigated in human primary dendritic cells (DC). A comparative analysis of transcriptome, signalling pathway activation, maturation, apoptosis, cytokine production and capacity to promote Th1 responses demonstrated that DC sense quantitative and qualitative differences in the expression of RD1-encoded factors--ESAT6 and CFP10--within BCG or Mtb backgrounds. Expansion of IFN-γ producing T cells was promoted by BCG::RD1-challenged DC, as compared to their BCG-infected counterparts. Although Mtb recombinants acted as a strong Th-1 promoting stimulus, even with RD1 deletion, the attenuated Mtb strain carrying a C-terminus truncated ESAT-6 elicited a robust Th1 promoting phenotype in DC. Collectively, these studies indicate a necessary but not sufficient role for the RD1 locus in promoting DC immune-regulatory functions. Additional mycobacterial factors are likely required to endow DC with a high Th1 polarizing capacity, a desirable attribute for a successful control of Mtb infection.
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Marilena P
authors.initials: MP
authors.lastname: Etna
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Giacomini
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pardini
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Severa
authors.affiliation: Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa; Pisa, Italy.|Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics; Paris, France.
authors.forename: Daria
authors.initials: D
authors.lastname: Bottai
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Cruciani
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rizzo
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences; University of Torino; Turin, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Calogero
authors.affiliation: Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics; Paris, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy.
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Coccia
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016296:Mutagenesis; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010641:Phenotype; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D059467:Transcriptome; D014614:Vaccines, Synthetic / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D051996:Transcription Factor RelA; D014614:Vaccines, Synthetic; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases