Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery
Year: 2025
Type: article
Abstract: Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.
DOI: 10.1084/jem.20250444
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Harvard University, Harvard University Center for AIDS Research, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, National Institutes of Health, Center for AIDS Research, University of Washington, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Environmental Health Sciences
Awards: G1203476693, Identification of adaptive response mechanisms in breast cancer by information theory and proteomics, G1575283533, G1722716446, G345173699, Training Grant in Environmental Toxicology, G7287189751, G7785852513, G9000129761, The MIT Superfund Research Program: A Systems Approach for the Protection of Human Health from Hazardous Chemicals, Harvard University Center for AIDS Research, Quantitative systems biology of glioblastoma cells and their interactions with the neuronal and immunological milieu, High-dimensional characterization of phagosome composition, control and phagocytic receptor redundancy
OpenAlex ID: W4412555687