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Sortases, Surface Proteins, and Their Roles in Staphylococcus aureus Disease and Vaccine Development.

ABSTRACT: Sortases cleave short peptide motif sequences at the C-terminal end of secreted surface protein precursors and either attach these polypeptides to the peptidoglycan of Gram-positive bacteria or promote their assembly into pilus structures that are also attached to peptidoglycan. Sortase A, the enzyme first identified in the human pathogen Staphylococcus aureus, binds LPXTG motif sorting signals, cleaves between threonine (T) and glycine (G) residues, and forms an acyl enzyme between its active-site cysteine thiol and the carboxyl group of threonine (T). Sortase A acyl enzyme is relieved by the nucleophilic attack of the cross bridge amino group within lipid II, thereby generating surface protein linked to peptidoglycan precursor. Such products are subsequently incorporated into the cell wall envelope by enzymes of the peptidoglycan synthesis pathway. Surface proteins linked to peptidoglycan may be released from the bacterial envelope to diffuse into host tissues and fulfill specific biological functions. S. aureus sortase A is essential for host colonization and for the pathogenesis of invasive diseases. Staphylococcal sortase-anchored surface proteins fulfill key functions during the infectious process, and vaccine-induced antibodies targeting surface proteins may provide protection against S. aureus. Alternatively, small-molecule inhibitors of sortase may be useful agents for the prevention of S. aureus colonization and invasive disease.

SUBMITTER: Schneewind O

PROVIDER: S-EPMC6386163 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Sortases, Surface Proteins, and Their Roles in <i>Staphylococcus aureus</i> Disease and Vaccine Development.

Schneewind Olaf O Missiakas Dominique D

Microbiology spectrum 20190101 1

Sortases cleave short peptide motif sequences at the C-terminal end of secreted surface protein precursors and either attach these polypeptides to the peptidoglycan of Gram-positive bacteria or promote their assembly into pilus structures that are also attached to peptidoglycan. Sortase A, the enzyme first identified in the human pathogen <i>Staphylococcus aureus</i>, binds LPXTG motif sorting signals, cleaves between threonine (T) and glycine (G) residues, and forms an acyl enzyme between its a ...[more]

PMID: 30737913

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Project description:A major hurdle in vaccine development is the difficulty in identifying relevant target epitopes and then presenting them to the immune system in a context that mimics their native conformation. We have engineered novel virus-like-particle (VLP) technology that is able to display complex libraries of random peptide sequences on a surface-exposed loop in the coat protein without disruption of protein folding or VLP assembly. This technology allows us to use the same VLP particle for both affinity selection and immunization, integrating the power of epitope discovery and epitope mimicry of traditional phage display with the high immunogenicity of VLPs. Previously, we showed that using affinity selection with our VLP platform identifies linear epitopes of monoclonal antibodies and subsequent immunization generates the proper antibody response. To test if our technology could identify immunologic mimotopes, we used affinity selection on a monoclonal antibody (AP4-24H11) that recognizes the Staphylococcus aureus autoinducing peptide 4 (AIP4). AIP4 is a secreted eight amino acid, cyclized peptide produced from the S. aureus accessory gene regulator (agrIV) quorum-sensing operon. The agr system coordinates density dependent changes in gene expression, leading to the upregulation of a host of virulence factors, and passive transfer of AP4-24H11 protects against S. aureus agrIV-dependent pathogenicity. In this report, we identified a set of peptides displayed on VLPs that bound with high specificity to AP4-24H11. Importantly, similar to passive transfer with AP4-24H11, immunization with a subset of these VLPs protected against pathogenicity in a mouse model of S. aureus dermonecrosis. These data are proof of principle that by performing affinity selection on neutralizing antibodies, our VLP technology can identify peptide mimics of non-linear epitopes and that these mimotope based VLP vaccines provide protection against pathogens in relevant animal models.

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Sortases, Surface Proteins, and Their Roles in Staphylococcus aureus Disease and Vaccine Development.

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Sortases, Surface Proteins, and Their Roles in <i>Staphylococcus aureus</i> Disease and Vaccine Development.

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Dataset Information

Sortases, Surface Proteins, and Their Roles in Staphylococcus aureus Disease and Vaccine Development.

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Sortases, Surface Proteins, and Their Roles in &lt;i&gt;Staphylococcus aureus&lt;/i&gt; Disease and Vaccine Development.

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Sortases, Surface Proteins, and Their Roles in <i>Staphylococcus aureus</i> Disease and Vaccine Development.