Identification of antigens presented by MHC for vaccines against tuberculosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB33057 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3376650_1.fastq.gz | Fastqsanger.gz | |||
| ERR3376650_2.fastq.gz | Fastqsanger.gz | |||
| ERR3376641_1.fastq.gz | Fastqsanger.gz | |||
| ERR3376641_2.fastq.gz | Fastqsanger.gz | |||
| ERR3376651_1.fastq.gz | Fastqsanger.gz |
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Project description:The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. We have purified MHC class-I and MHC-II peptides and analysed them by mass spectrometry. We have successfully identified 97 mycobacterial peptides presented by MHC-II and 54 presented by MHC-I, from 76 and 41 antigens, respectively. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cells from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying novel candidate antigens.
2020-01-08 | E-MTAB-8057 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.
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Project description:Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading cause of infectious disease mortality worldwide for which no sufficiently protective vaccine exists. CD8+ T cells contribute to protective immunity to TB, but the antigenic targets presented on MHC-I by macrophages infected with virulent Mtb for recognition by CD8+ T cells have not been conclusively defined. Here, we use mass spectrometry to directly identify Mtb-derived peptides presented on MHC class I (MHC-I) by infected primary human monocyte-derived macrophages. We identified 16 MHC-I peptides derived from 12 Mtb proteins, and validated these identifications using internal standard parallel reaction monitoring (SureQuant). Our results show that this set of antigens is highly enriched for substrates of type VII secretion systems (T7SS) relative to the Mtb proteome. Our results identify specific Mtb proteins that may be suitable targets for subunit vaccines designed to elicit protective CD8+ T cell-mediated immunity and suggest that T7SS substrates may be a fruitful class of antigens to prioritize for further vaccine target discovery efforts. Note: donors labeled A, C, D, E, H, and I in file names here are renamed sequentially (A, B, C, D, E, and F) in the manuscript describing this study to avoid confusion.
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