title: An unbiased genome-wide Mycobacterium tuberculosis gene expression approach to discover antigens targeted by human T cells expressed during pulmonary infection.
abstract: Mycobacterium tuberculosis is responsible for almost 2 million deaths annually. Mycobacterium bovis bacillus Calmette-Guérin, the only vaccine available against tuberculosis (TB), induces highly variable protection against TB, and better TB vaccines are urgently needed. A prerequisite for candidate vaccine Ags is that they are immunogenic and expressed by M. tuberculosis during infection of the primary target organ, that is, the lungs of susceptible individuals. In search of new TB vaccine candidate Ags, we have used a genome-wide, unbiased Ag discovery approach to investigate the in vivo expression of 2170 M. tuberculosis genes during M. tuberculosis infection in the lungs of mice. Four genetically related but distinct mouse strains were studied, representing a spectrum of TB susceptibility controlled by the supersusceptibility to TB 1 locus. We used stringent selection approaches to select in vivo-expressed M. tuberculosis (IVE-TB) genes and analyzed their expression patterns in distinct disease phenotypes such as necrosis and granuloma formation. To study the vaccine potential of these proteins, we analyzed their immunogenicity. Several M. tuberculosis proteins were recognized by immune cells from tuberculin skin test-positive, ESAT6/CFP10-responsive individuals, indicating that these Ags are presented during natural M. tuberculosis infection. Furthermore, TB patients also showed responses toward IVE-TB Ags, albeit lower than tuberculin skin test-positive, ESAT6/CFP10-responsive individuals. Finally, IVE-TB Ags induced strong IFN-γ(+)/TNF-α(+) CD8(+) and TNF-α(+)/IL-2(+) CD154(+)/CD4(+) T cell responses in PBMC from long-term latently M. tuberculosis-infected individuals. In conclusion, these IVE-TB Ags are expressed during pulmonary infection in vivo, are immunogenic, induce strong T cell responses in long-term latently M. tuberculosis-infected individuals, and may therefore represent attractive Ags for new TB vaccines.
authors: Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
authors: Susanna
authors: S
authors: Commandeur
authors: Krista E
authors: KE
authors: van Meijgaarden
authors: Corine
authors: C
authors: Prins
authors: Alexander V
authors: AV
authors: Pichugin
authors: Karin
authors: K
authors: Dijkman
authors: Susan J F
authors: SJ
authors: van den Eeden
authors: Annemieke H
authors: AH
authors: Friggen
authors: Kees L M C
authors: KL
authors: Franken
authors: Gregory
authors: G
authors: Dolganov
authors: Igor
authors: I
authors: Kramnik
authors: Gary K
authors: GK
authors: Schoolnik
authors: Fredrik
authors: F
authors: Oftung
authors: Gro Ellen
authors: GE
authors: Korsvold
authors: Annemieke
authors: A
authors: Geluk
authors: Tom H M
authors: TH
authors: Ottenhoff
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology*; D018390:Gene Targeting / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology*; D015203:Reproducibility of Results; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology
chemical_list: D000942:Antigens, Bacterial; D032581:Tuberculosis Vaccines