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: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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Project description:Colorectal cancer is the second leading cause of cancer death worldwide, and the incidence of this disease is expected to increase as global socioeconomic changes occur. Immune checkpoint inhibition therapy is effective in treating a minority of colorectal cancer tumors; however, microsatellite stable tumors do not respond well to this treatment. Emerging cancer immunotherapeutic strategies aim to activate a cytotoxic T cell response against tumor-specific antigens, presented exclusively at the cell surface of cancer cells. These antigens are rare and are most effectively identified with a mass spectrometry-based approach, which allows the direct sampling and sequencing of these peptides. While the few tumor-specific antigens identified to date derived from coding regions of the genome, recent findings indicate that a large proportion of tumor-specific antigens originate from allegedly noncoding regions. Here, we employed a novel proteogenomic approach to identify tumor antigens in a collection of colorectal cancer-derived cell lines and biopsy samples consisting of matched tumor and normal adjacent tissue. The generation of personalized cancer databases paired with mass spectrometry analyses permitted the identification of more than 30 000 unique MHC I-associated peptides. We identified 19 putative tumor-specific antigens in both microsatellite stable and unstable tumors, over two-thirds of which were derived from non-coding regions. Many of these peptides were derived from source genes known to be involved in colorectal cancer progression, suggesting that antigens from these genes could have therapeutic potential in a wide range of tumors. These findings could benefit the development of T cell-based vaccines, in which T cells are primed against these antigens to target and eradicate tumors. Such a vaccine could be used in tandem with existing immune checkpoint inhibition therapies, to bridge the gap in treatment efficacy across subtypes of colorectal cancer with varying prognoses.
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