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      Identification of a protective B-cell epitope of the Staphylococcus aureus GapC protein by screening a phage-displayed random peptide library

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          Abstract

          The impact of epidemic Staphylococcus aureus ( S. aureus) on public health is increasing. Because of the abuse of antibiotics, the antibiotic resistance of S. aureus is increasing. Thus, there is an urgent need to develop new immunotherapies and immunoprophylaxes. Previous studies showed that the GapC protein of S. aureus, which is a surface protein with high glyceraldehyde 3-phosphate dehydrogenase activity, transferrin binding activity, and other biological activities, is highly conserved. GapC induces an effective humoral immune response in vivo. However, the B-cell epitopes of S. aureus GapC have not been well identified. Here we used the bioinformatics tools to analyze the sequence of GapC, and we generated protective anti-GapC monoclonal antibodies (mAbs). A protective mAb (1F4) showed strong specificity to GapC and the ability to induce macrophages to phagocytose S. aureus. We screened the motif 272GYTEDEIVSSD 282, which was recognized by mAb 1F4, using a phage display system. Then, we used site-directed mutagenesis to identify key amino acids in the motif. Residues G272 D276 E277 I278 and V279 formed the core of the 272GYTEDEIVSSD 282 motif. In addition, we showed that this epitope peptide induced a protective humoral immune response against S. aureus infection in immunized mice. Our results will be useful for the further study of epitope-based vaccines against S. aureus infection.

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          Most cited references35

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          Surface protein adhesins of Staphylococcus aureus.

          T. Foster (1998)
          Staphylococcus aureus can colonize the host to initiate infection by adhering to components of the extracellular matrix. Adherence is mediated by surface protein adhesins (MSCRAMMs). Ligand binding by these fibronectin-, fibrinogen- and collagen-binding proteins occurs by distinct mechanisms that are being investigated at the molecular level.
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            VanA-type vancomycin-resistant Staphylococcus aureus.

            Since 2002, nine methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains that are also resistant to vancomycin (VRSA) have been reported in the United States, including seven clinical isolates from Michigan. The strains harbor a plasmid-borne Tn1546 element following conjugation from a glycopeptide-resistant Enterococcus strain. In the second step, Tn1546 transposed to a resident plasmid in five strains; the acquired plasmid behaved as a suicide gene delivery vector, and the incoming DNA had been rescued by illegitimate recombination. Surprisingly, combination of a glycopeptide with a beta-lactam has a strong synergistic effect against VRSA, both in vitro and in an animal model, despite resistance of the strains to both drug classes when administered separately. This results from the fact that the late peptidoglycan precursors ending in D-alanine-D-lactate (D-Ala-D-Lac) that are mainly synthesized in the presence of glycopeptide inducers are not substrates for PBP2', which is the only transpeptidase that remains active in the presence of oxacillin. One VRSA strain is partially dependent on vancomycin for growth due to a mutation in the host D-Ala:D-Ala ligase, thus having to rely on the inducible resistance pathway for cell wall synthesis. Competition growth experiments in the absence of inducer between the MRSA recipient and isogenic VRSA transconjugant revealed a disadvantage for the transconjugant, accounting, in part, for the low level of dissemination of the VRSA clinical isolates. The association of multiple molecular and environmental factors has been implicated in the regional emergence of VRSA in Michigan.
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              Vaccine assembly from surface proteins of Staphylococcus aureus.

              Staphylococcus aureus is the most common cause of hospital-acquired infection. Because of the emergence of antibiotic-resistant strains, these infections represent a serious public health threat. To develop a broadly protective vaccine, we tested cell wall-anchored surface proteins of S. aureus as antigens in a murine model of abscess formation. Immunization with four antigens (IsdA, IsdB, SdrD, and SdrE) generated significant protective immunity that correlated with the induction of opsonophagocytic antibodies. When assembled into a combined vaccine, the four surface proteins afforded high levels of protection against invasive disease or lethal challenge with human clinical S. aureus isolates.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draft
                Role: Methodology
                Role: MethodologyRole: Software
                Role: Formal analysisRole: Methodology
                Role: Methodology
                Role: Methodology
                Role: Methodology
                Role: Project administration
                Role: Data curationRole: Software
                Role: Data curationRole: MethodologyRole: Software
                Role: Methodology
                Role: Software
                Role: Data curation
                Role: Resources
                Role: MethodologyRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 January 2018
                2018
                : 13
                : 1
                : e0190452
                Affiliations
                [1 ] College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, P.R. China
                [2 ] College of Animal Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, P.R. China
                Instituto Butantan, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-34030
                10.1371/journal.pone.0190452
                5755776
                29304128
                e1ec4242-3c0f-4c14-b57d-1a5167bfbe47
                © 2018 Wang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 October 2017
                : 14 December 2017
                Page count
                Figures: 8, Tables: 2, Pages: 17
                Funding
                Funded by: Natural Science Foundation of Heilongjiang Province of China
                Award ID: ZD2016004
                Award Recipient :
                Funded by: Research Innovation Program for College Graduates of Heilongjiang Bayi Agricultural University
                Award ID: YJSCX2017-Y62
                Award Recipient :
                This work was supported by Natural Science Foundation of Heilongjiang Province of China (ZD2016004) and Research Innovation Program for College Graduates of Heilongjiang Bayi Agricultural University (YJSCX2017-Y62).
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