Core proteome mining of Salmonella enterica subsp. enterica to explore novel therapeutic targets and design a multi-epitope vaccine

Salmonella enterica subsp. enterica (S. enterica) infects humans and animals, causing enteric and systemicsalmonellosis. Antibiotics are no longer effective against S. enterica infection due to the advent of multidrugresistant(MDR) strains. Additionally, typhoid vaccines are not currently advised for children under the ageof six, and their long-term efficacy is questionable. In the present study, we employed a bioinformaticspipeline of subtractive proteomics and immunoinformatics to explore novel drug and vaccine targets andconstruct a multi-epitope vaccine against S. enterica. A total of ۱۹۶۴ protein-coding sequences were retrievedfrom the EDGAR database that comprised the core genome of ۱۸۵ S. enterica strains. The core genome wasscreened for non-paralogous proteins employing CD-HIT tool which resulted in ۱۹۴۹ protein sequences.Subtractive proteomics prioritized twenty-seven cytoplasmic and six outer membrane proteins (OMPs) aspotential drug and vaccine targets, respectively based on their non-homology to humans, presence ofessential, virulent and resistant factors, interaction to host (Homo sapiens), and role in pathogen-specificmetabolic pathways. The OMPs with low molecular weight, transmembrane helices, and high antigenicitywere subjected to immunoinformatics analysis to identify cytotoxic T lymphocyte (CTL) epitopes, helper Tlymphocyte (HTL) epitopes, and linear B lymphocyte (LBL) epitopes using various tools and servers. Thehighly antigenic, non-allergenic and non-toxic epitopes were selected to design four different vaccineconstructs (VC۱, VC۲, VC۳, and VC۴) using linkers and immune-modulating adjuvants. The vaccineconstruct (VC۴) was selected based on its physicochemical properties, allergenicity, antigenicity, and nontoxicitypotential. The molecular docking and molecular dynamics (MD) simulation analyses ensured stablemolecular interaction of the final prioritized vaccine construct with human immune cell receptors (TLR۴).Finally, the vaccine construct (VC۴) was cloned in silico to ensure its effectiveness. We conclude that thedesigned vaccine construct may provide immunological protection against S. enterica infections.

Keywords:

Cytotoxic T lymphocytes (CTL) epitopes , Helper T lymphocytes (HTL) epitopes , Immunoinformatics , In silico cloning , Linear B lymphocyte (LBL) epitopes , Molecular docking , Molecular dynamics (MD) simulation , Multidrug-resistance (MDR) , Multiepitope-based subunit vaccine , Outer membrane proteins (OMPs) , Subtractive proteomics