IMMUNOPEPTIDOMICS · Global immunopeptidome landscape of normal and Mycobacterium tuberculosis-infected human cells

Global immunopeptidome landscape of normal and Mycobacterium tuberculosis-infected human cells

The cells of the immune system protect us by recognizing telltale molecules produced by damaged and diseased cells, or by infection-causing microorganisms (which are also called pathogens). To help with this process, the cells in our bodies display small fragments of proteins (called peptides) on their surface that are then checked by the immune cells. Collectively, these peptides are referred to as the ‘immunopeptidome’ and deciphering the complexity of the human immunopeptidome is important for both basic research and medical science. The general goal of the ‘IMMUNOPEPTPIDOMICS’ project is to apply state of the art mass spectrometry technologies for the measurement of immunopeptidomes in health and diseases. More precisely, the first research objective of the proposal aims at investigating the relationship between the immunopeptidome and the proteome on a global scale. The second objective of the proposal consists at identifying a large number of Mycobacterium tuberculosis (Mtb)-derived peptides in the immunopeptidome of Mtb-infected cells. To achieve these objectives, I have followed my research plan as proposed and I have explored and prioritized a number of new opportunities in line with the general goal of my project. The IMMUNOPEPTIDOMICS project has produced research results of high quality that were subsequently published in top international journals. The work performed and the main results achieved so far are listed below: - Publications: In Caron et al. (eLife, 2015), we present a novel mass spectrometry-based high-throughput workflow and an open-source computational and data resource to reproducibly identify and quantify MHC-associated peptides. Collectively, the resources support the generation of MHC allele-specific peptide assay libraries consisting of consensus fragment ion spectra, and the analysis of quantitative digital maps of MHC immunopeptidomes generated from a range of biological sources by SWATH mass spectrometry (MS). In Gubin et al. (Nature, 2014), we applied a groundbreaking targeted mass spectrometry approach to detect mutated MHC class I peptides in cancer cells. In Caron et al. (MCP, in press), we summarize established isolation techniques as well as emerging mass spectrometry-based platforms (i.e. SWATH-MS) to identify and quantify MHC-associated peptides. In Rosenberger et al. (Scientific Data, 2014), we generated a repository of assays for the quantification of 10,000 human proteins using SWATH mass spectrometry. In Esterhuysea et al. (mBio, 2015), we integrated for the first time proteomics, epigenetics and transcriptomics data in the quest for tuberculosis biomarkers. - The research results of IMMUNOPEPTIDOMICS facilitated the launch of the Human Immuno-Peptidome Project (HIPP) as part of the Biology and Disease-Driven Groups of the Human Proteome Project (B/D-HPP). The long-term objective of the HIPP is to make accessible robust analysis of immunopeptidomes to any immunologist. The international consortium is composed of about 15 group leaders so far. See https://www.hupo.org/human-immuno-peptidome-project-hipp/ - Knowledge transfer to international level through new research collaborations with University of Tübingen (Tübingen, Germany), Washington University - School of Medicine (St-Louis, MO, USA), Monash University (Clayton, Australia), Max Planck Institute of Biochemistry (Munich, Germany), La Jolla Institute for Allergy and Immunology (La Jolla, CA, USA), University of Oxford (Oxford, United Kingdom), Pacific Northwest National Laboratory (Richmond, USA) and Spanish National Biotechnology Centre (Madrid, Spain). - Knowledge transfer through interviews for faculty position: 1) Washington University School of Medicine (St-Louis, MO, USA), and 2) University of Lausanne (Lausanne, Switzerland). - Knowledge transfer through presentation of the project to international conferences, workshops and meetings. Follow up activities plan for the next year as a continuation of the IMMUNOPEPTIDOMICS project (funded by TBVAC2020/TBVI - HORIZON2020): - Ongoing work: a new method for the isolation of MHC-associated is currently under development in collaboration with Tobias Weiss from University of Zurich. The method combines size exclusion chromatography and targeted mass spectrometry. - Ongoing work: active collaboration with Dr. Michal Bassani-Sternberg (CHUV-UNIL, Lausanne, Switzerland) and Prof. Stefan Kaufmann (Max Planck Institute for Infection Biology, Berlin, Germany) for the identification of new MHC-associated peptides encoded by Mtb genomes. - Ongoing work: a study to generate a tissue-based map of the mouse immunopeptidome is currently conducted in collaboration with the group of Prof. Hans Georg Rammensee (Tübingen, Germany). The relationship between the proteome and the immunopeptidome will be assessed in this context. - Ongoing work: in collaboration with the Functional Genomics Center (Zurich, Switzerland), we are currently automating the computational workflow developed and initially described in Caron et al. (eLife, 2015). The computational workflow will provide the community a platform for generating high quality MHC allele-specific peptide assay libraries. Data generated by the community will be stored in the SWATHAtlas database for its continuous expansion. We also plan to bridge the data in the SWATHAtlas database with the data in the Immune Epitope Database (IEDB) in collaboration with Prof. Alex Sette (La Jolla, CA, USA). Overall, IMMUNOPEPTIDOMICS promote the worldwide application of the emerging SWATH mass spectrometry technology towards reproducible and quantitative measurements of peptides presented by MHC/HLA molecules, an essential step to accelerate the development of next-generation immune-based therapies. If further developed, we believe that IMMUNOPEPTIDOMICS and future related projects will enable more successful vaccine design against autoimmune diseases, cancers, AIDS, tuberculosis, malaria as well as new and emerging diseases of the 21st century.

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