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Delineating the Immuno-Dominant Antigenic Vaccine Peptides Against gacS-Sensor Kinase in Acinetobacter baumannii: An in silico Investigational Approach.

ABSTRACT: Objectives:To predict the novel vaccine peptide candidates against gacS protein involved with the citrate utilization in the two-component system of A. baumannii-associated virulence as an alternative strategy to combat the multi-drug resistant strains using an immuno-informatic approach. Methods:The study is designed as an observational in silico study design with the application of BepiPred, AlgPred, VaxiJen, AntigenPro, SolPro, Expasy ProtParam server, IEDB database, and MHC cluster analytical tools and servers to predict the immuno-dominant B-cell and T-cell epitopes from gacS FASTA sequences retrieved from UNIPROT database. Further peptide interactions with TLR-4 was assessed based on the number of hydrogen bonds. Results:Nine peptides (20aa) with the highest score of 1 were selected from the 137 epitopes, and five were predicted as antigenic epitopes (E1-E5). E3 was selected as the potent antigen (score: 0.939537) and E1 as the best vaccine candidate (score: 0.9803) under AntigenPro and Vaxijen server, respectively. SolPro predicted all epitopes as soluble peptides. ProtParam predictions showed E3 and E5 as stable proteins with a shelf life of 3.5 and 1.9 h and possessed negative GRAVY values. PsortB server predicted a final localization score of 7.88 for the gacS protein sequence as a cytoplasmic membrane protein. IEDB conservancy analysis showed 100% conserved sequences within the gacS sequence, and class I conservancy yielded positive values for all epitopes. Cluster analysis showed strong interactions, and the protein-peptide interactions with TLR-2 finally detected E5 as the best interacting peptide (H bonds = 14) followed by E3 (H bonds = 12). Conclusion:The study suggests five antigenic peptides as promiscuous vaccine candidates to target the gacS of A. baumannii using immuno-informatic approach toward the peptide synthesis and in vitro analysis. However, the study recommends further experimental validation for immunological response and memory through in vivo studies.

SUBMITTER: Smiline Girija AS

PROVIDER: S-EPMC7506167 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Delineating the Immuno-Dominant Antigenic Vaccine Peptides Against gacS<i>-</i>Sensor Kinase in <i>Acinetobacter baumannii</i>: An <i>in silico</i> Investigational Approach.

Smiline Girija A S AS

Frontiers in microbiology 20200908

<h4>Objectives</h4>To predict the novel vaccine peptide candidates against gacS protein involved with the citrate utilization in the two-component system of <i>A. baumannii</i>-associated virulence as an alternative strategy to combat the multi-drug resistant strains using an immuno-informatic approach.<h4>Methods</h4>The study is designed as an observational <i>in silico</i> study design with the application of BepiPred, AlgPred, VaxiJen, AntigenPro, SolPro, Expasy ProtParam server, IEDB databa ...[more]

PMID: 33013757

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Project description:Nosocomial infections have become alarming with the increase of multidrug-resistant bacterial strains of Acinetobacter baumannii. Being the causative agent in ~80% of the cases, these pathogenic gram-negative species could be deadly for hospitalized patients, especially in intensive care units utilizing ventilators, urinary catheters, and nasogastric tubes. Primarily infecting an immuno-compromised system, they are resistant to most antibiotics and are the root cause of various types of opportunistic infections including but not limited to septicemia, endocarditis, meningitis, pneumonia, skin, and wound sepsis and even urinary tract infections. Conventional experimental methods including typing, computational methods encompassing comparative genomics, and combined methods of reverse vaccinology and proteomics had been proposed to differentiate and develop vaccines and/or drugs for several outbreak strains. However, identifying proteins suitable enough to be posed as drug targets and/or molecular vaccines against the multidrug-resistant pathogenic bacterial strains has probably remained an open issue to address. In these cases of novel protein identification, the targets either are uncharacterized or have been unable to confer the most coveted protection either in the form of molecular vaccine candidates or as drug targets. Here, we report a strategic approach with the 3,766 proteins from the whole genome of A. baumannii ATCC19606 (AB) to rationally identify plausible candidates and propose them as future molecular vaccine candidates and/or drug targets. Essentially, we started with mapping the vaccine candidates (VaC) and virulence factors (ViF) of A. baumannii strain AYE onto strain ATCC19606 to identify them in the latter. We move on to build small networks of VaC and ViF to conceptualize their position in the network space of the whole genomic protein interactome (GPIN) and rationalize their candidature for drugs and/or molecular vaccines. To this end, we propose new sets of known proteins unearthed from interactome built using key factors, KeF, potent enough to compete with VaC and ViF. Our method is the first of its kind to propose, albeit theoretically, a rational approach to identify crucial proteins and pose them for candidates of vaccines and/or drugs effective enough to combat the deadly pathogenic threats of A. baumannii.

Project description:BackgroundAcinetobacter baumannii has emerged as a significant nosocomial pathogen during the last few years, exhibiting resistance to almost all major classes of antibiotics. Alternative treatment options such as vaccines tend to be most promising and cost effective approaches against this resistant pathogen. In the current study, we have explored the pan-genome of A. baumannii followed by immune-proteomics and reverse vaccinology approaches to identify potential core vaccine targets.ResultsThe pan-genome of all available A. baumannii strains (30 complete genomes) is estimated to contain 7,606 gene families and the core genome consists of 2,445 gene families (~32 % of the pan-genome). Phylogenetic tree, comparative genomic and proteomic analysis revealed both intra- and inter genomic similarities and evolutionary relationships. Among the conserved core genome, thirteen proteins, including P pilus assembly protein, pili assembly chaperone, AdeK, PonA, OmpA, general secretion pathway protein D, FhuE receptor, Type VI secretion system OmpA/MotB, TonB dependent siderophore receptor, general secretion pathway protein D, outer membrane protein, peptidoglycan associated lipoprotein and peptidyl-prolyl cis-trans isomerase are identified as highly antigenic. Epitope mapping of the target proteins revealed the presence of antigenic surface exposed 9-mer T-cell epitopes. Protein-protein interaction and functional annotation have shown their involvement in significant biological and molecular processes. The pipeline is validated by predicting already known immunogenic targets against Gram negative pathogen Helicobacter pylori as a positive control.ConclusionThe study, based upon combinatorial approach of pan-genomics, core genomics, proteomics and reverse vaccinology led us to find out potential vaccine candidates against A. baumannii. The comprehensive analysis of all the completely sequenced genomes revealed thirteen putative antigens which could elicit substantial immune response. The integration of computational vaccinology strategies would facilitate in tackling the rapid dissemination of resistant A.baumannii strains. The scarcity of effective antibiotics and the global expansion of sequencing data making this approach desirable in the development of effective vaccines against A. baumannii and other bacterial pathogens.

Project description:Introduction A. baumannii is categorized as a priority pathogen due to its propensity for multi-drug resistance, exhibiting resistance against the last resort of antibiotics. It is also considered a potent nosocomial pathogen, so targeting the microbe using novel strategies would be the need of the hour. In this context, the in-silico computational approach would serve the best to design the possible epitope peptides, which may be further considered for the experimental trials for their immunological response. Objective: To predict the immune-dominant epitope peptide candidates against the bfmR and bfmS proteins mediating the two-component system adaptation in the formation of biofilm in A. baumannii.Materials and methods11 different FASTA sequences of bfmR and bfmS from A. baumannii strains retrieved based on the blast-p similarity search tool were subjected to linear epitope B-cell epitope predictions under the IEDB B-cell epitope prediction server. Further analysis on antigenicity, allergenicity, and toxigenicity was achieved using the AntigenPro, Vaxijen, and AlgPred tools, with the physical and chemical properties evaluated using the Expasy Protparam server. Selection of the immunodominant peptides for T-cells was done through the databases under IEDB. The final assessment of protein-TLR2 interactions was done by MHC cluster servers.ResultsFour peptide sequences (E1-E4) were predicted for B-cell dominance, with E1, E2, and E4 as probable antigens. All were soluble and non-toxigenic. E1 and E3 were considered non-allergens. GRAVY values were negative for all the peptides, indicating the protein to be hydrophilic in nature. Analysis of the T-cell epitopes was promising, with 100% conservancy for class-I HLA alleles, high interaction scores for similarity with TLR2, and more hydrogen bonds for E2, followed by other epitope peptides.ConclusionThe promising four epitopes, as predicted for bfmR and bfmS in the present study, suggest their potent role as possible candidates for the design of vaccines targeting the TCS of A. baumannii, recommending further in vitro and in vivo experimental validation.

Dataset Information

Delineating the Immuno-Dominant Antigenic Vaccine Peptides Against gacS-Sensor Kinase in Acinetobacter baumannii: An in silico Investigational Approach.

Publications

Delineating the Immuno-Dominant Antigenic Vaccine Peptides Against gacS<i>-</i>Sensor Kinase in <i>Acinetobacter baumannii</i>: An <i>in silico</i> Investigational Approach.

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