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Targeting CD4 + T cell epitopes conserved across bacterial species for broadly acting bacterial vaccines

ABSTRACT: Antimicrobial resistance is a global health threat, and alternative therapeutic interventions to replace failing antibiotics are urgently needed. Vaccines are effective tools to combat bacterial infection and mitigate multi-drug resistance, however, the selection of bacterial antigens as vaccine candidates remains challenging. Here we use immunopeptidomics to mine for CD4 T-cell vaccine targets in methicillin-resistant Staphylococcus aureus - a clinically significant, antibiotic-resistant bacterium that is susceptible to T cell meditated control. We identified a novel, highly conserved, immunodominant CD4 T cell epitope in S. aureus that is derived from the core DNA binding protein Hu (Hup). This epitope is shared across a range of clinically relevant bacteria and cross-species reactive Hup specific CD4 T cells are found in both mice and humans. Immunisation with the Hup epitope resulted in the development of broadly protective CD4 T cell immunity capable of limiting disease severity following infection with different bacterial species, including S. aureus and Streptococcus pneumoniae. A vaccine incorporating antigenic targets derived from conserved core genes that are shared across bacterial species, can confer broad spectrum protection against a range of clinically significant bacteria, including antibiotic-resistant strains.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Staphylococcus Aureus (ncbitaxon:1280) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Linda Wakim

PROVIDER: MSV000100384 | MassIVE | Mon Jan 05 21:50:00 GMT 2026

SECONDARY ACCESSION(S): PXD072694

REPOSITORIES: MassIVE

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Project description:Heinemann2005 - Genome-scale reconstruction of Staphylococcus aureus (iMH551) This model is described in the article: In silico genome-scale reconstruction and validation of the Staphylococcus aureus metabolic network. Heinemann M, Kümmel A, Ruinatscha R, Panke S. Biotechnol. Bioeng. 2005 Dec; 92(7): 850-864 Abstract: A genome-scale metabolic model of the Gram-positive, facultative anaerobic opportunistic pathogen Staphylococcus aureus N315 was constructed based on current genomic data, literature, and physiological information. The model comprises 774 metabolic processes representing approximately 23% of all protein-coding regions. The model was extensively validated against experimental observations and it correctly predicted main physiological properties of the wild-type strain, such as aerobic and anaerobic respiration and fermentation. Due to the frequent involvement of S. aureus in hospital-acquired bacterial infections combined with its increasing antibiotic resistance, we also investigated the clinically relevant phenotype of small colony variants and found that the model predictions agreed with recent findings of proteome analyses. This indicates that the model is useful in assisting future experiments to elucidate the interrelationship of bacterial metabolism and resistance. To help directing future studies for novel chemotherapeutic targets, we conducted a large-scale in silico gene deletion study that identified 158 essential intracellular reactions. A more detailed analysis showed that the biosynthesis of glycans and lipids is rather rigid with respect to circumventing gene deletions, which should make these areas particularly interesting for antibiotic development. The combination of this stoichiometric model with transcriptomic and proteomic data should allow a new quality in the analysis of clinically relevant organisms and a more rationalized system-level search for novel drug targets. This model is hosted on BioModels Database and identified by: MODEL1507180072. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Targeting CD4 + T cell epitopes conserved across bacterial species for broadly acting bacterial vaccines

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