title: New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles.
abstract: New strategies are needed to develop better tools to control TB, including identification of novel antigens for vaccination. Such Mtb antigens must be expressed during Mtb infection in the major target organ, the lung, and must be capable of eliciting human immune responses. Using genome-wide transcriptomics of Mtb infected lungs we developed data sets and methods to identify IVE-TB (in-vivo expressed Mtb) antigens expressed in the lung. Quantitative expression analysis of 2,068 Mtb genes from the predicted first operons identified the most upregulated IVE-TB genes during in-vivo pulmonary infection. By further analysing high-level conservation among whole-genome sequenced Mtb-complex strains (n = 219) and algorithms predicting HLA-class-Ia and II presented epitopes, we selected the most promising IVE-TB candidate antigens. Several of these were recognized by T-cells from in-vitro Mtb-PPD and ESAT6/CFP10-positive donors by proliferation and multi-cytokine production. This was validated in an independent cohort of latently Mtb-infected individuals. Significant T-cell responses were observed in the absence of IFN-γ-production. Collectively, the results underscore the power of our novel antigen discovery approach in identifying Mtb antigens, including those that induce unconventional T-cell responses, which may provide important novel tools for TB vaccination and biomarker profiling. Our generic approach is applicable to other infectious diseases.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Coppola
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Krista E
authors.initials: KE
authors.lastname: van Meijgaarden
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susanna
authors.initials: S
authors.lastname: Commandeur
authors.affiliation: Department Microbiology Immunology, Stanford Univ. School of Medicine, Stanford, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dolganov
authors.affiliation: Department Immunology Infectious Diseases, Harvard School of Public Health, Boston, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.affiliation: Department Microbiology Immunology, Stanford Univ. School of Medicine, Stanford, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schoolnik
authors.affiliation: Institute of Biomedicine of Valencia (IBV-CSIC), Valencia, Spain.|CIBER in Epidemiology and Public Health, Madrid, Spain.
authors.forename: Inaki
authors.initials: I
authors.lastname: Comas
authors.affiliation: Dept. Systems Biology, Technical Univ., Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Lund
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Corine
authors.initials: C
authors.lastname: Prins
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susan J F
authors.initials: SJ
authors.lastname: van den Eeden
authors.affiliation: Department of Infectious Disease Immunology, Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Gro E
authors.initials: GE
authors.lastname: Korsvold
authors.affiliation: Department of Infectious Disease Immunology, Domain for Infection Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oftung
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Geluk
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000465:Algorithms; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D049109:Cell Proliferation; D015331:Cohort Studies; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000942:Antigens, Bacterial; D016207:Cytokines; D016056:Immunodominant Epitopes; C072681:Mycobacterium tuberculosis antigens