Structure of ScpC, a virulence protease from Streptococcus pyogenes, reveals the functional domains and maturation mechanism

2018 ◽  
Vol 475 (17) ◽  
pp. 2847-2860 ◽  
Author(s):  
Chacko Jobichen ◽  
Ying Chong Tan ◽  
Mahalakshmi Tirumuru Prabhakar ◽  
Digant Nayak ◽  
Debabrata Biswas ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Group A Streptococcus ◽  
Structural Rearrangement ◽  
Functional Domains ◽  
Active Site Residues ◽  
Inhibitor Complex ◽  
Wide Range ◽  
Significant Difference ◽  
Streptococcal Species ◽  
Group A

Group A Streptococcus (GAS; Streptococcus pyogenes) causes a wide range of infections, including pharyngitis, impetigo, and necrotizing fasciitis, and results in over half a million deaths annually. GAS ScpC (SpyCEP), a 180-kDa surface-exposed, subtilisin-like serine protease, acts as an essential virulence factor that helps S. pyogenes evade the innate immune response by cleaving and inactivating C-X-C chemokines. ScpC is thus a key candidate for the development of a vaccine against GAS and other pathogenic streptococcal species. Here, we report the crystal structures of full-length ScpC wild-type, the inactive mutant, and the ScpC–AEBSF inhibitor complex. We show ScpC to be a multi-domain, modular protein consisting of nine structural domains, of which the first five constitute the PR + A region required for catalytic activity. The four unique C-terminal domains of this protein are similar to collagen-binding and pilin proteins, suggesting an additional role for ScpC as an adhesin that might mediate the attachment of S. pyogenes to various host tissues. The Cat domain of ScpC is similar to subtilisin-like proteases with significant difference to dictate its specificity toward C-X-C chemokines. We further show that ScpC does not undergo structural rearrangement upon maturation. In the ScpC–inhibitor complex, the bound inhibitor breaks the hydrogen bond between active-site residues, which is essential for catalysis. Guided by our structure, we designed various epitopes and raised antibodies capable of neutralizing ScpC activity. Collectively, our results demonstrate the structure, maturation process, inhibition, and substrate recognition of GAS ScpC, and reveal the presence of functional domains at the C-terminal region.

Lipid Peptide Core Nanoparticles as Multivalent Vaccine Candidates against Streptococcus pyogenes

2012 ◽  
Vol 65 (1) ◽  
pp. 35 ◽  
Author(s):  
Mariusz Skwarczynski ◽  
Bibi Hamideh Parhiz ◽  
Fatemeh Soltani ◽  
Saranya Srinivasan ◽  
Khairul A. Kamaruzaman ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Subunit Vaccine ◽  
Click Reaction ◽  
Group A Streptococcus ◽  
Vaccine Candidates ◽  
Wide Range ◽  
Group A ◽  
Core Peptide ◽  
Aqueous Conditions ◽  
Peptide Core

Traditional vaccine approaches for Group A streptococcus (GAS) infection are inadequate owing to the host’s production of cross-reactive antibodies that recognize not only the bacteria but also human tissue. To overcome this problem a peptide subunit-based vaccine was proposed, which would incorporate only minimal non-cross reactive epitopes. However, special delivery systems/adjuvants were required because short peptides are not immunogenic. In this study we have incorporated two epitopes from two different GAS proteins into a lipid core peptide (LCP) self-adjuvanting delivery system to achieve better protection against a wide range of GAS serotypes. Multivalent and monovalent constructs were synthesized with the help of an azide alkyne cycloaddition (click) reaction and their ability to self-assemble under aqueous conditions was examined. The compounds significantly differed in their ability to form small size nanoparticles, which are believed to be most appropriate for peptide-based subunit vaccine delivery. The LCP conjugates possessing two different epitopes, in contrast to monoepitopic constructs, formed small nanoparticles (5–15 nm) presumably owing to a suitable hydrophilic-hydrophobic balance of the molecules.

scholarly journals Asymptomatic throat carriage rate and antimicrobial resistance pattern of Streptococcus pyogenes in Nepalese school children

1970 ◽  
Vol 7 (4) ◽  
pp. 392-396 ◽  
Author(s):  
SP Dumre ◽  
K Sapkota ◽  
M Adhikari ◽  
D Acharya ◽  
M Karki ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Streptococcus Pyogenes ◽  
School Children ◽  
Group A Streptococcus ◽  
Health Concern ◽  
Diffusion Method ◽  
Antibiotics Resistance ◽  
Carriage Rate ◽  
Significant Difference ◽  
Group A

Background: Streptococcus pyogenes or Group A streptococcus (GAS) causes several suppurative and non suppurative infections. In addition to pharyngitis and skin infections, GAS are also the causative agent of post-streptococcal infection syndromes such as acute rheumatic fever (ARF) and post-streptococcal glumerulonephritis (PSG). GAS frequently colonises in the throat of an asymptomatic person. Pharyngeal carriage rates of GAS among healthy school children vary with geographical location and seasons. Objectives: We carried out this preliminary study to determine the throat carriage rate and antimicrobial resistance trend of Streptococcus pyogenes or Group A streptococcus (GAS) among the Nepalese school children. Materials and methods: Four schools situated at different locations of Kathmandu valley were included in the study. Throat swabs from 350 students of age group 5-15 years were collected, immediately transported to the laboratory and were processed for S. pyogenes following standard microbiological procedures. Antimicrobial susceptibility testing of the isolates was performed by Kirby Bauer disc diffusion method following CLSI guidelines. Results: S. pyogenes was isolated from 10.9% (38/350) of the screened children. The GAS colonisation rate was statistically insignificant (P>0.05) with sex and age sub-groups, although the rate was slightly higher among girls and age sub-group 9-12 years. No significant difference in carrier rate was observed among different schools (P>0.05). All isolates were susceptible to azithromycin. No resistance was detected for penicillin and its derivative antibiotic ampicillin. Highest resistance rate was observed for cotrimoxazole (71.0%) followed by chloramphenicol (7.8%), ciprofl oxacin (5.2%) and erythromycin (5.2%). Conclusion: Antibiotic resistant GAS isolated from asymptomatic Nepalese school children is a public health concern. When screened and appropriately treated with antibiotics, carriers can be prevented from spreading of streptococcal infections in the school environment and the community. Preventing cross infections would ultimately reduce the incidence of life-threatening sequelae which are debilitating and difficult to treat. It is recommended to conduct regular screening and GAS surveillance in schools, and maintain rational use of antibiotics to minimise GAS carriage/infections and resistance. Key words: Streptococcus pyogenes; Antibiotics Resistance; Throat carriage; Children; Nepal. DOI: 10.3126/kumj.v7i4.2760 Kathmandu University Medical Journal (2009) Vol.7, No.4 Issue 28, 392-396

Etiology, clinical presentation, laboratory diagnostics, pathogenesis of impetigo and treatment methods

2020 ◽  
pp. 64-70
Author(s):  
Anastasiya Laknitskaya
Keyword(s):  
Streptococcus Pyogenes ◽  
Skin Diseases ◽  
Group A Streptococcus ◽  
Antibiotic Sensitivity ◽  
Antioxidant Defense System ◽  
Laboratory Diagnostics ◽  
Treatment Methods ◽  
Group A ◽  
The Individual

Currently, one of the priority medical and social problems is the optimization of treatment methods for pyoderma associated with Streptococcus pyogenes — group A streptococcus (GAS). To date, the proportion of pyoderma, the etiological factor of which is Streptococcus pyogenes, is about 6 % of all skin diseases and is in the range from 17.9 to 43.9 % of all dermatoses. Role of the bacterial factor in the development of streptococcal pyoderma is obvious. Traditional treatment complex includes antibacterial drugs selected individually, taking into account the antibiotic sensitivity of pathognomonic bacteria, and it is not always effective. Currently implemented immunocorrection methods often do not take into account specific immunological features of the disease, the individual, and the fact that the skin performs the function of not only a mechanical barrier, but it is also an immunocompetent organ. Such an approach makes it necessary to conduct additional studies clarifying the role of factors of innate and adaptive immunity, intercellular mediators and antioxidant defense system, that allow to optimize the treatment of this pathology.

scholarly journals Association between Resistance to Erythromycin and the Presence of the Fibronectin Binding Protein F1 Gene, prtF1, in Streptococcus pyogenes Isolates from German Pediatric Patients

2005 ◽  
Vol 49 (7) ◽  
pp. 2990-2993 ◽  
Author(s):  
Maria Haller ◽  
Kirsten Fluegge ◽  
Sandra Jasminder Arri ◽  
Brit Adams ◽  
Reinhard Berner
Keyword(s):  
Streptococcus Pyogenes ◽  
Pediatric Patients ◽  
Group A Streptococcus ◽  
Binding Protein ◽  
Macrolide Resistance ◽  
Group A ◽  
Fibronectin Binding Protein ◽  
Fibronectin Binding ◽  
Cell Invasiveness

ABSTRACT A total of 301 German pediatric group A streptococcus isolates were screened for the presence of macrolide resistance and the fibronectin binding protein F1 gene (prtF1) encoding an adhesin and cell invasiveness protein. The prtF1 gene was present significantly more often among macrolide-resistant isolates. The majority of these were not clonally related.

scholarly journals Biochemical and biological activity of arginine deiminase from Streptococcus pyogenes M22

2016 ◽  
Vol 94 (2) ◽  
pp. 129-137 ◽  
Author(s):  
Eleonora A. Starikova ◽  
Alexey V. Sokolov ◽  
Anna Yu. Vlasenko ◽  
Larisa A. Burova ◽  
Irina S. Freidlin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Streptococcus Pyogenes ◽  
Group A Streptococcus ◽  
Bacterial Pathogen ◽  
Arginine Deiminase ◽  
Dependent Manner ◽  
Group A ◽  
Micro Organisms ◽  
Dose Dependent

Streptococcus pyogenes (group A Streptococcus; GAS) is an important gram-positive extracellular bacterial pathogen responsible for a number of suppurative infections. This micro-organism has developed complex virulence mechanisms to avoid the host’s defenses. We have previously reported that SDSC from GAS type M22 causes endothelial-cell dysfunction, and inhibits cell adhesion, migration, metabolism, and proliferation in a dose-dependent manner, without affecting cell viability. This work aimed to isolate and characterize a component from GAS type M22 supernatant that suppresses the proliferation of endothelial cells (EA.hy926). In the process of isolating a protein possessing antiproliferative activity we identified arginine deiminase (AD). Further study showed that this enzyme is most active at pH 6.8. Calculating Km and Vmax gave the values of 0.67 mmol·L–1 and 42 s−1, respectively. A distinctive feature of AD purified from GAS type M22 is that its optimum activity and the maximal rate of the catalytic process is close to neutral pH by comparison with enzymes from other micro-organisms. AD from GAS type M22 suppressed the proliferative activity of endothelial cells in a dose-dependent mode. At the same time, in the presence of AD, the proportion of cells in G0/G1 phase increased. When l-Arg was added at increasing concentrations to the culture medium containing AD (3 μg·mL–1), the enzyme’s capacity to inhibit cell proliferation became partially depressed. The proportion of cells in phases S/G2 increased concomitantly, although the cells did not fully recover their proliferation activity. This suggests that AD from GAS type M22 has potential for the suppression of excessive cell proliferation.

scholarly journals Analysis of virulence factors and emm typing of Streptococcus pyogenes clinical isolates.

2019 ◽  
Author(s):  
Gustavo Enck Sambrano ◽  
Gustavo P Riboldi ◽  
Keli C Reiter ◽  
Thiago Galvão da Silva Paim ◽  
Neidmar Correa Tolfo ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Streptococcus Pyogenes ◽  
Virulence Genes ◽  
Clinical Isolates ◽  
Pcr Analysis ◽  
Tissue Tropism ◽  
Factors Analysis ◽  
Wide Range ◽  
Group A ◽  
Micro Organisms

Background: Streptococcus pyogenes, a Group A streptococci (GAS), is an important human pathogen that causes a wide range of infections. Methods: Twenty five clinical isolates of S. pyogenes were submitted to an emm typing and to a Real-time PCR analysis for 23 important virulence factors. Results: Fourteen emm types were found and the emm1 type was the most prevalent. The majority of the isolates were classified as emm pattern E, followed by A-C3. No pattern D was found. Among the virulence factors, the most prevalent were SpeG, Slo, C5a-peptidase and SPNA. Phage encoded virulence genes were also found among the strains, such as mf-2, SpeJ and SpeL. Discussion: The emm1 type was the most prevalent while the 13 others M types were distributed along the strains. No tissue tropism was found on the isolates. The virulence factors analysis demonstrated that chromosomally and phage-encoded genes were found, which confers a potential for high virulent micro-organisms.

scholarly journals Analysis of virulence factors and emm typing of Streptococcus pyogenes clinical isolates.

2019 ◽  
Author(s):  
Gustavo Enck Sambrano ◽  
Gustavo P Riboldi ◽  
Keli C Reiter ◽  
Thiago Galvão da Silva Paim ◽  
Neidmar Correa Tolfo ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Streptococcus Pyogenes ◽  
Virulence Genes ◽  
Clinical Isolates ◽  
Pcr Analysis ◽  
Tissue Tropism ◽  
Factors Analysis ◽  
Wide Range ◽  
Group A ◽  
Micro Organisms

Background: Streptococcus pyogenes, a Group A streptococci (GAS), is an important human pathogen that causes a wide range of infections. Methods: Twenty five clinical isolates of S. pyogenes were submitted to an emm typing and to a Real-time PCR analysis for 23 important virulence factors. Results: Fourteen emm types were found and the emm1 type was the most prevalent. The majority of the isolates were classified as emm pattern E, followed by A-C3. No pattern D was found. Among the virulence factors, the most prevalent were SpeG, Slo, C5a-peptidase and SPNA. Phage encoded virulence genes were also found among the strains, such as mf-2, SpeJ and SpeL. Discussion: The emm1 type was the most prevalent while the 13 others M types were distributed along the strains. No tissue tropism was found on the isolates. The virulence factors analysis demonstrated that chromosomally and phage-encoded genes were found, which confers a potential for high virulent micro-organisms.

scholarly journals Host Pathways of Hemostasis that Regulate Group A Streptococcus pyogenes Pathogenicity

2020 ◽  
Vol 21 (2) ◽  
pp. 193-201
Author(s):  
Victoria A. Ploplis ◽  
Francis J. Castellino
Keyword(s):  
Streptococcus Pyogenes ◽  
Inflammatory Responses ◽  
Group A Streptococcus ◽  
Protein A ◽  
M Protein ◽  
Severe Group ◽  
Group A ◽  
Flow Through ◽  
Hallmark Feature ◽  
Major Target

A hallmark feature of severe Group A Streptococcus pyogenes (GAS) infection is dysregulated hemostasis. Hemostasis is the primary pathway for regulating blood flow through events that contribute towards clot formation and its dissolution. However, a number of studies have identified components of hemostasis in regulating survival and dissemination of GAS. Several proteins have been identified on the surface of GAS and they serve to either facilitate invasion to host distal sites or regulate inflammatory responses to the pathogen. GAS M-protein, a surface-exposed virulence factor, appears to be a major target for interactions with host hemostasis proteins. These interactions mediate biochemical events both on the surface of GAS and in the solution when M-protein is released into the surrounding environment through shedding or regulated proteolytic processes that dictate the fate of this pathogen. A thorough understanding of the mechanisms associated with these interactions could lead to novel approaches for altering the course of GAS pathogenicity.

scholarly journals Immediate vs. delayed toe-to-thumb transfer: Is the infection rate greater?

2019 ◽  
Vol 51 (06) ◽  
pp. 434-439
Author(s):  
Matteo Ornelli ◽  
Giovanni Ruocco ◽  
Juste Kaciulyte ◽  
Lara Lazzaro ◽  
Nicola Felici
Keyword(s):  
Infection Rate ◽  
Infection Rates ◽  
Immediate Reconstruction ◽  
Wide Range ◽  
Significant Difference ◽  
Group A ◽  
Group B ◽  
Toe Transfer ◽  
Delayed Reconstruction ◽  
Reconstruction Group

Abstract Background After loss of a thumb, the big toe is a possible donor site for reconstruction with wrap-around free flap and trimmed-toe transfer techniques. Early reconstructions seem to reduce the risk of post-operative infections, despite several studies that show different infection rates of the recipient site in immediate toe-to-hand transfer. The authors carried out a retrospective analysis of their experience in thumb reconstruction with big toe transfer and evaluated the results achieved with both immediate and delayed reconstructions in terms of infection occurrence. Patients and Methods From 2000 to 2017, patients who presented cut, crush and avulsion injuries in the thumb were selected and 33 toe-to-thumb transfers were performed. Patients were divided into two groups: in group A, patients underwent immediate reconstruction, while in group B delayed reconstructions were performed. The two groups received identical antimicrobial prophylaxis. Reliability of the immediate or delayed reconstruction was compared in terms of flap survival, requirement for a secondary intention healing and, in particular, rate of infection. Results 29 male and 4 female patients were treated. Toe-to-thumb transfers were performed in both groups: in group A, 8 wrap-around free flaps and 4 trimmed toe transfers; in group B, 11 wrap-around and 10 trimmed toe transfers. No flap loss occurred in either groups. No cases of infection were detected in the transferred toes. Conclusion For toe-to-thumb transfer, there are published reports of a wide range of infection rates of the recipient sites. The authors compared their results in terms of infection rate between immediate reconstruction, group A, and delayed reconstruction, group B. Immediate toe-to-thumb transfer showed equal success rates to delayed transfer. No statistically significant difference in risk of infection between the two groups was found. Results showed that the immediate reconstruction was as safe and reliable as the delayed one.

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