Novel Conserved Group A Streptococcal Proteins Identified by the Antigenome Technology as Vaccine Candidates for a Non-M Protein-Based Vaccine

Fritzer, Andrea; Senn, Beatrice M.; Minh, Duc Bui; Hanner, Markus; Gelbmann, Dieter; Noiges, Birgit; Henics, Tamás; Schulze, Kai; Guzmán, Carlos A.; Goodacre, John; Gabain, Alexander von; Nagy, Eszter; Meinke, Andreas

doi:10.1128/iai.00295-10

Cited by 61 publications

(71 citation statements)

References 67 publications

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“…In Streptococcus pyogenes, Spy1356, the SepM homolog, has multiple functions. Spy1356 is crucial for surface expression of various proteins, including M protein, and responsible for binding with the extracellular matrix proteins (13). Further studies are necessary to unravel the range of processes regulated by SepM and its homologs in other Grampositive organisms.…”

Section: Discussionmentioning

confidence: 99%

“…SepM processes synthetic CSP. SepM is predicted to be a membrane-associated protein, and its ortholog in group A streptococcus (GAS) is localized on the surface (13,47). Since a putative Lon-like protease domain is encoded within the sequence, we speculated that SepM might be involved in the postexport maturation of CSP-21.…”

Section: Fig 2 Effect Of Synthetic Csp On Pnlma Expression and Transfmentioning

confidence: 99%

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An Extracelluar Protease, SepM, Generates Functional Competence-Stimulating Peptide in Streptococcus mutans UA159

2012

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Cell-cell communication in Gram-positive bacteria often depends on the production of extracellular peptides. The cariogenic bacterium Streptococcus mutans employs so-called competence-stimulating peptide (CSP) to stimulate mutacin (bacteriocin) production and competence development through the activation of the ComDE two-component pathway. In S. mutans, CSP is secreted as a 21-residue peptide; however, mass spectrometric analysis of culture supernatant indicates the presence of an 18-residue proteolytically cleaved species. In this study, using a transposon mutagenesis screening, we identified a cell surface protease that is involved in the processing of 21-residue CSP to generate the 18-residue CSP. We named this protease SepM for streptococcal extracellular protease required for mutacin production. We showed that the truncated 18-residue peptide is the biologically active form and that the specific postexport cleavage is a prerequisite to activate the ComDE two-component signal transduction pathway. We also showed that the CSP and the mutacins are exported outside the cell by the same ABC transporter, NlmTE. Our study further confirmed that the ComDE two-component system is absolutely necessary for mutacin production in S. mutans. Quorum sensing is a primary means of bacterial communication that often uses secreted peptide pheromones to regulate expression of various genes when the bacterial cell density reaches a certain threshold concentration. Numerous cellular processes, such as virulence factor expression, extracellular enzyme production, antibiotic production, biofilm formation, and genetic exchange, are regulated by quorum sensing (25,38,48,54,55). In streptococci, competence-stimulating peptide (CSP)-mediated quorum sensing is a prerequisite for development of competence that leads to cellular DNA uptake from the surroundings for genetic diversity (41). The Gram-positive pathogen Streptococcus mutans, a primary causative agent of dental caries, employs a wellconserved quorum-sensing system called ComCDE that coordinates the expression of bacteriocins encoding genes and stimulates development of genetic competence (22,23,30,40,51,57). The ComCDE-regulated quorum-sensing system has also been implicated in regulation of biofilm formation (30) and stress responses (28) in addition to other cellular processes.Gram-positive bacteria use ribosomally synthesized peptides as quorum-signaling molecules (31). These peptides are typically translated as prepeptides that undergo processing during export to the extracellular environment (48). In S. mutans UA159, the peptide pheromone CSP is encoded by comC as a prepeptide with a leader sequence containing a conserved double glycine (GG) motif. During secretion through a dedicated ABC transporter complex, the N-terminal leader peptide is cleaved off by the proteolytic activity of the transporter to generate a mature peptide that is 21 residues long (CSP-21) (15,30,43). When the extracellular CSP concentration reaches a certain threshold, ComD, a membrane-associated hi...

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Section: Discussionmentioning

confidence: 99%

Section: Fig 2 Effect Of Synthetic Csp On Pnlma Expression and Transfmentioning

confidence: 99%

An Extracelluar Protease, SepM, Generates Functional Competence-Stimulating Peptide in Streptococcus mutans UA159

2012

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“…Demonstrating the robustness of this technology, SpyCEP has been identified as a protective GAS antigen in multiple studies employing GAS reverse vaccinology (582,587,588). One such study used trypsin to "shave" surface-exposed proteins, which were subsequently identified by proteomics (588).…”

Section: Gas Reverse Vaccinologymentioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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SUMMARY Streptococcus pyogenes , also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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“…Therefore, the development of efficacious vaccines against obligate and facultative intracellular pathogens depends largely upon the ability to identify antigen formulations that induce effective B-and T-cell responses (1)(2)(3). Although both genomic and proteomic strategies have been applied successfully to discover B-cell-stimulating vaccines (4)(5)(6)(7), the identification of antigens eliciting effector T cells generally is considered less amenable to high-throughput approaches.…”

mentioning

confidence: 99%

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

Finco

Frigimelica

Buricchi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Natural immunity against obligate and/or facultative intracellular pathogens is usually mediated by both humoral and cellular immunity. The identification of those antigens stimulating both arms of the immune system is instrumental for vaccine discovery. Although high-throughput technologies have been applied for the discovery of antibody-inducing antigens, few examples of their application for T-cell antigens have been reported. We describe how the compilation of the immunome, here defined as the pool of immunogenic antigens inducing T- and B-cell responses in vivo, can lead to vaccine candidates against Chlamydia trachomatis . We selected 120 C. trachomatis proteins and assessed their immunogenicity using two parallel high-throughput approaches. Protein arrays were generated and screened with sera from C. trachomatis -infected patients to identify antibody-inducing antigens. Splenocytes from C. trachomatis -infected mice were stimulated with 79 proteins, and the frequency of antigen-specific CD4 + /IFN-γ + T cells was analyzed by flow cytometry. We identified 21 antibody-inducing antigens, 16 CD4 + /IFN-γ + –inducing antigens, and five antigens eliciting both types of responses. Assessment of their protective activity in a mouse model of Chlamydia muridarum lung infection led to the identification of seven antigens conferring partial protection when administered with LTK63/CpG adjuvant. Protection was largely the result of cellular immunity as assessed by CD4 + T-cell depletion. The seven antigens provided robust additive protection when combined in four-antigen combinations. This study paves the way for the development of an effective anti- Chlamydia vaccine and provides a general approach for the discovery of vaccines against other intracellular pathogens.

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Novel Conserved Group A Streptococcal Proteins Identified by the Antigenome Technology as Vaccine Candidates for a Non-M Protein-Based Vaccine

Cited by 61 publications

References 67 publications

An Extracelluar Protease, SepM, Generates Functional Competence-Stimulating Peptide in Streptococcus mutans UA159

An Extracelluar Protease, SepM, Generates Functional Competence-Stimulating Peptide in Streptococcus mutans UA159

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

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