Streptococcal Cysteine Protease-Mediated Cleavage of Desmogleins Is Involved in the Pathogenesis of Cutaneous Infection

Sumitomo, Tomoko; Mori, Yasushi; Nakamura, Yuumi; Honda-Ogawa, Mariko; Nakagawa, Satoko; Yamaguchi, M.; Matsue, Hiroyuki; Terao, Yutaka; Nakata, Masao; Kawabata, Shigetada

doi:10.3389/fcimb.2018.00010

Cited by 27 publications

(20 citation statements)

References 41 publications

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“…It causes a wide range of infections from pharyngitis to severe systemic diseases, such as necrotizing fasciitis or streptococcal toxic shock syndrome (STSS), and post-infection complications ( Cunningham, 2000 ; Pires et al, 2012 ). Moreover, S. pyogenes causes extensive cutaneous infections ranging from superficial cellulitis to severe cellulitis, and even life-threatening pyoderma ( Sumitomo et al, 2018 ). Group A streptococci (GAS) phage-associated pyrogenic exotoxins or superantigens ( Jing et al, 2006 ) have been shown to cause severe diseases such as scarlet fever, rheumatic fever, and rheumatic heart diseases ( Rato et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning and Docking of speB Gene Encoding Cysteine Protease With Antibiotic Interaction in Streptococcus pyogenes NBMKU12 From the Clinical Isolates

et al. 2018

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Streptococcus pyogenes causes a variety of diseases ranging from mild diseases to severe invasive infections which result in significant morbidity and mortality. This study focuses on the antibiotic resistance of S. pyogenes and their interaction with cysteine protease. Around 36 beta-hemolytic isolates were collected from the clinical lab, of which seven isolates (19.4%) were identified as Streptococcus pyogenes. One of the seven isolates was collected from a urinary tract infection, which was identified by antibody agglutination and MALTI-TOF-MS, and it is designated as S. pyogenes NBMKU12. Around 8.3 to 66.6 % of the isolates were found to be resistant to one or more antimicrobial agents, especially, penicillin-G resistance was exhibited by 29.1% of the isolates. In the NBMKU12 isolate, the beta lactem (TEM) gene was detected among the 13 antibiotic genes for which it was tested. Furthermore, when analysis for presence of 13 virulence genes were carried out in NBMKU12 isolate, only speJ and speB were detected. The speB (streptococcal pyrogenic exotoxin B) encoding cysteine protease gene was cloned. This was followed by performing DNA sequencing to understand the putative cysteine protease interaction with antibiotics, inhibitors, and substrate. The speB gene consists of 1197 nucleotides and encodes a protein with multiple domains, including a signal peptide (aa 1–22), an inhibitor region (aa 27–156), and a catalytic cysteine domain (aa 160–367). The signal peptide cleavage site is predicted between Ala22 and Asn23. The putative 398 amino acid residues were found to have a theoretical pI of 8.76 and a molecular mass of 43,204.36 Da. The tested culture supernatants of NBMKU12 isolate exhibited the proteolytic activity against casein, papaya and pineapple used as substrates. The proteolytic activity suggests the expression of speB gene. Molecular docking analysis of cysteine protease showed that erythromycin (bond length 2.41 Å), followed by chloramphenicol (2.51 Å), exhibited a strong interaction; while penicillin-G (3.24 Å) exhibited a weak interaction, and this factor could be considered as a cause for penicillin-G resistance. The present study contributes to a better understanding of speB gene encoding cysteine protease, antibiotic resistance, and their interaction in the isolate, S. pyogenes NBMKU12. The antibiotics and cysteine protease interaction study confirms the resistance or sensitivity of S. pyogenes. Hence, it could be hypothesized that the isolate NBMKU12 is resistant to most of the tested antibiotics, and this resistance might be a cause for mutation.

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Section: Introductionmentioning

confidence: 99%

Molecular Cloning and Docking of speB Gene Encoding Cysteine Protease With Antibiotic Interaction in Streptococcus pyogenes NBMKU12 From the Clinical Isolates

et al. 2018

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“…Streptolysin S (SLS; encoded by sagA-I ) and SpeB (encoded by speB ) are widely recognized virulence factors of S. pyogenes [38]. SLS is involved in cellular injury, phagocytic resistance, and virulence in murine subcutaneous infection [39, 40], and SLS and SpeB promote S. pyogenes translocation via a paracellular route by degrading epithelial junctions [41, 42]. SpeB is a secreted cysteine protease degrading a wide variety of host proteins including complement components and cytokines, and functions in escape of S. pyogenes from host immune response [43–47].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of Streptococcus pyogenes M1T1 strain in a mouse model of necrotizing fasciitis

Hirose

Yamaguchi

Okuzaki

et al. 2019

Preprint

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Streptococcus pyogenes is a major cause of necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection. At the host infection site, the local environment and interaction between host and bacteria affect bacterial gene-expression profiles, but the S. pyogenes gene-expression pattern in necrotizing fasciitis remains unknown. In this study, we used a mouse model of necrotizing fasciitis and performed RNA-sequencing (RNA-seq) analysis of S. pyogenes M1T1 strain 5448 by using infected hindlimbs obtained at 24, 48, and 96 h post-infection. The RNA-seq analysis identified 483 bacterial genes whose expression was consistently altered in the infected hindlimbs as compared to their expression under in vitro conditions. The consistently enriched genes during infection included 306 genes encoding molecules involved in virulence, carbohydrate utilization, amino acid metabolism, trace-metal transport and vacuolar ATPase transport system. Surprisingly, drastic upregulation of 3 genes, encoding streptolysin S precursor (sagA), cysteine protease (speB), and secreted DNase (spd), was noted in the mouse model of necrotizing fasciitis (log2 fold-change values: >6.0, >9.4, and >7.1, respectively). Conversely, the consistently downregulated genes included 177 genes, containing genes associated with oxidative-stress response and cell division. These results suggest that S. pyogenes in necrotizing fasciitis changes its metabolism, decreases cell proliferation, and upregulates the expression of major toxins. Our findings could provide critical information for developing novel treatment strategies and vaccines for necrotizing fasciitis.Author summaryNecrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, principally caused by a Streptococcus pyogenes. At infection sites in hosts, bacterial pathogens are exposed to drastically changing environmental conditions and alter global gene expression patterns for survival and pathogenesis. However, there is no previous report about transcriptomic profiling of S. pyogenes in the necrotizing fasciitis. Here, we conducted comprehensive gene-expression analyses of S. pyogenes in the mouse model of necrotizing fasciitis at three distinct time points during infection. Our results indicated that S. pyogenes drastically upregulates the expression of virulence-associated genes and shifts metabolic-pathway usage during infection. The high-level expressions in particular of toxins, such as cytolysins, proteases, and nucleases, were observed at infection sites. In addition, the consistently enriched genes identified here included genes for metabolism of arginine and histidine, and carbohydrate uptake and utilization. Conversely, the genes associated with oxidative-stress response and cell division were consistently downregulated in the mouse model of necrotizing fasciitis. These data will provide useful information necessary for establishing novel treatment strategies (166 words).

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“…We determined whether HylD is involved in skin infection considering that SDSE is omnipresent on human skin. SDSE cannot invade normal mouse skin because it lacks the speB gene that encodes for the cysteine protease SpeB, which is critically important for mouse skin invasion (Lukomski et al, 1999;Sumitomo et al, 2018). In this study, we tested a skin wound infection model with SDSE.…”

Section: Skin Wound Infection With Sdsementioning

confidence: 99%

Novel Hyaluronate Lyase Involved in Pathogenicity of Streptococcus dysgalactiae subsp. equisimilis

et al. 2020

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Streptococcus dysgalactiae subsp. equisimilis (SDSE) causes cellulitis, bacteremia, and invasive diseases, such as streptococcal toxic shock syndrome. Although SDSE infection is more prevalent among elderly individuals and those with diabetes mellitus than infections with Streptococcus pyogenes (Group A streptococci; GAS) and Streptococcus agalactiae (Group B streptococci; GBS), the mechanisms underlying the pathogenicity of SDSE remain unknown. SDSE possesses a gene hylD encoding a hyaluronate lyase (HylD), whose homologue (HylB) is involved in pathogenicity of GBS, while the role of HylD has not been characterized. In this study, we focused on the enzyme HylD produced by SDSE; HylD cleaves hyaluronate (HA) and generates unsaturated disaccharides via a β-elimination reaction. Hyaluronate-agar plate assays revealed that SDSE promoted dramatic HA degradation. SDSE expresses both HylD and an unsaturated glucuronyl hydrolase (UGL) that catalyzes the degradation of HA-derived oligosaccharides; as such, SDSE was more effective at HA degradation than other β-hemolytic streptococci, including GAS and GBS. Although HylD shows some homology to HylB, a similar enzyme produced by GBS, HylD exhibited significantly higher enzymatic activity than HylB at pH 6.0, conditions that are detected in the skin of both elderly individuals and those with diabetes mellitus. We also detected upregulation of transcripts from hylD and ugl genes from SDSE wild-type collected from the mouse peritoneal cavity; upregulated expression of ugl was not observed in ΔhylD SDSE mutants. These results suggested that disaccharides produced by the actions of HylD are capable of triggering downstream pathways that catalyze their destruction. Furthermore, we determined that infection with SDSEΔhylD was significantly less lethal than infection with the parent strain. When mouse skin wounds were infected for 2 days, intensive infiltration of neutrophils was observed around the wound areas Nguyen et al.

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Streptococcal Cysteine Protease-Mediated Cleavage of Desmogleins Is Involved in the Pathogenesis of Cutaneous Infection

Cited by 27 publications

References 41 publications

Molecular Cloning and Docking of speB Gene Encoding Cysteine Protease With Antibiotic Interaction in Streptococcus pyogenes NBMKU12 From the Clinical Isolates

Molecular Cloning and Docking of speB Gene Encoding Cysteine Protease With Antibiotic Interaction in Streptococcus pyogenes NBMKU12 From the Clinical Isolates

Transcriptomic profiling of Streptococcus pyogenes M1T1 strain in a mouse model of necrotizing fasciitis

Novel Hyaluronate Lyase Involved in Pathogenicity of Streptococcus dysgalactiae subsp. equisimilis

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