The interaction of streptococcal inhibitor of complement (SIC) and its proteolytic fragments with the human beta defensins

Fernie-King, Barbara A.; Seilly, David J.; Lachmann, P. J.

doi:10.1111/j.0019-2805.2004.01837.x

Cited by 66 publications

(64 citation statements)

References 18 publications

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“…However, when the reciprocal experiment was performed, with LL-37 as the bound substrate, no interaction was observed. A similar result was reported by Fernie-King et al (12) for interactions between SIC and h␤D-2. They suggested that the difference between the two configurations of the assay was attributable to the masking of binding sites when a small molecule (i.e., h␤D-2; 64 amino acids) was bound to a plate.…”

Section: Discussionsupporting

confidence: 90%

“…SIC is found in only two S. pyogenes emm types, emm1 and emm57, and was first reported as a ligand for the complement proteins C6 and C7, inhibiting the formation of the membrane attack complex, thereby blocking complement-mediated lysis (10,11). SIC was subsequently shown to inhibit the antimicrobial activity of numerous AMPs and proteins, including LL-37, lysozyme, secretory leukocyte proteinase inhibitor (SLPI), and human ␣ and ␤ defensins (12,13). Additionally, SIC is inhibitory to the antimicrobial activity of several chemokines which are secreted on the pharyngeal epithelial surface (14).…”

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confidence: 99%

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DrsG from Streptococcus dysgalactiae subsp. equisimilis Inhibits the Antimicrobial Peptide LL-37

et al. 2014

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e SIC and DRS are related proteins present in only 4 of the >200 Streptococcus pyogenes emm types. These proteins inhibit complement-mediated lysis and/or the activity of certain antimicrobial peptides (AMPs). A gene encoding a homologue of these proteins, herein called DrsG, has been identified in the related bacterium Streptococcus dysgalactiae subsp. equisimilis. Here we show that geographically dispersed isolates representing 14 of 50 emm types examined possess variants of drsG. However, not all isolates within the drsG-positive emm types possess the gene. Sequence comparisons also revealed a high degree of conservation in different S. dysgalactiae subsp. equisimilis emm types. To examine the biological activity of DrsG, recombinant versions of two major DrsG variants, DrsGS and DrsGL, were expressed and purified. Western blot analysis using antisera raised to these proteins demonstrated both variants to be expressed and secreted into culture supernatants. Unlike SIC, but similar to DRS, DrsG does not inhibit complement-mediated lysis. However, like both SIC and DRS, DrsG is a ligand of the cathelicidin LL-37 and is inhibitory to its bactericidal activity in in vitro assays. Conservation of prolines in the C-terminal region also suggests that these residues are important in the biology of this family of proteins. This is the first report demonstrating the activity of an AMP-inhibitory protein in S. dysgalactiae subsp. equisimilis and suggests that inhibition of AMP activity is the primary function of this family of proteins. The acquisition of the complement-inhibitory activity of SIC may reflect its continuing evolution.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

DrsG from Streptococcus dysgalactiae subsp. equisimilis Inhibits the Antimicrobial Peptide LL-37

et al. 2014

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“…The role of Sic and SpeB in the growth of GAS in human saliva. GAS elaborates at least two extracellular proteins, SpeB and Sic, that have been shown to inhibit or inactivate the purified forms of antimicrobial peptides present in saliva (13,14,16,47). Sic is produced mainly by serotype M1 strains, whereas virtually all strains have the speB gene, although protein expression levels are variable (16,27,52).…”

Section: Discussionmentioning

confidence: 99%

Growth Characteristics of and Virulence Factor Production by Group A Streptococcus during Cultivation in Human Saliva

et al. 2005

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Group A Streptococcus (GAS) commonly infects the human oropharynx, but the initial molecular events governing this process are poorly understood. Saliva is a major component of the innate and acquired immune defense in this anatomic site. Although landmark studies were done more than 60 years ago, investigation of GAS-saliva interaction has not been addressed extensively in recent years. Serotype M1 GAS strain MGAS5005 cultured in human saliva grew to ϳ10 7 CFU/ml and, remarkably, maintained this density for up to 28 days. Strains of several other M-protein serotypes had similar initial growth patterns but did not maintain as high a CFU count during prolonged culture. As revealed by analysis of the growth of isogenic mutant strains, the ability of GAS to maintain high numbers of CFU/ml during the prolonged stationary phase in saliva was dependent on production of streptococcal inhibitor of complement (Sic) and streptococcal pyrogenic exotoxin B (SpeB). During cultivation in human saliva, GAS had growth-phase-dependent production of multiple proven and putative extracellular virulence factors, including Sic, SpeB, streptococcal pyrogenic exotoxin A, Mac protein, and streptococcal phospholipase A 2 . Our results clearly show that GAS responds in a complex fashion to growth in human saliva, suggesting that the molecular processes that enhance colonization and survival in the upper respiratory tract of humans are well under way before the organism reaches the epithelial cell surface.One hallmark of a successful microorganism is the ability to adapt to new host environments. Group A Streptococcus (GAS) causes a wide variety of diseases in humans, ranging from impetiginous skin lesions to invasive diseases, such as necrotizing fasciitis and meningitis. GAS is particularly suited to inhabit the human oropharynx, colonizing as many as onehalf of school-age children in nonepidemic periods and causing an estimated 15 million cases of pharyngitis in the United States each year (3,43). Moreover, the presence of GAS in the oropharynx generally is required for the subsequent development of rheumatic fever, the leading cause of preventable heart disease in children (10, 28).The oropharynx is the major site of entry for GAS into the human body and its main portal of transmission (19,43,46). Saliva is ubiquitous in the human oropharynx and is an essential part of both the acquired and innate immune defense systems (25,39). Landmark experiments conducted more than 60 years ago demonstrated the important role played by saliva in the establishment of GAS infection and the subsequent transmission of infectious organisms (18)(19)(20). These studies revealed that large numbers of live GAS were present in the saliva of individuals with GAS pharyngitis (19). Moreover, it was established that a major route for dissemination of GAS from infected individuals into the environment was via dispersal of aerosolized saliva (20). Other investigators have reported that pharyngitis patients with detectable levels of GAS in their saliva were more l...

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“…After centrifugation at 1700 × g for 10 min, 1.0 ml of the supernatant was withdrawn and mixed with 1.0 ml of NaOH 0.5 M, and absorbance at 440 nm was measured. Bactericidal Activity --The bactericidal activity toward E. faecalis was assayed using the method of Fernie-King et al 21) The bacterial cells were harvested at the mid-log phase and suspended in 10 mM of Tris-HCl buffer supplemented with 52-fold diluted MRS broth (buffer C, pH 7.5) at the cell density of 2 × 10 5 CFU/ml. An aliquot of the bacterial cell suspension (15 µl) was mixed with an equal volume of HNP-3 (0-2.0 µM) or HD-5 (0-0.25 µM), and the mixture was incubated at 37 • C for 2 hr.…”

Section: Bacterialmentioning

confidence: 99%

Defensive Effects of Human Antimicrobial Peptide .ALPHA.-Defensins against Enterococcus faecalis

Miyoshi

Koyama

Mizuno

et al. 2010

JOURNAL OF HEALTH SCIENCE

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Cationic and amphiphilic antimicrobial peptides (AMPs) such as α-defensins and cathelicidins are factors related to innate immunity. In the present study, we examined the protective effects of two AMPs, human neutrophil peptide-3 and α-defensin-5, against the opportunistic pathogen Enterococcus faecalis (E. faecalis). The α-defensins had dose-dependent bactericidal activity, whereas they showed no synergistic effect on the antimicrobial actions of antibiotics. Although AMPs often neutralize bacterial bioactive products, neither α-defensin reduced the proteolytic activity of GelE, a toxic protease from E. faecalis. On the other hand, the α-defensins were found to be fairly stable even in the presence of excess amounts of GelE. These results indicate that α-defensins may be defensive factors against E. faecalis in humans.

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The interaction of streptococcal inhibitor of complement (SIC) and its proteolytic fragments with the human beta defensins

Cited by 66 publications

References 18 publications

DrsG from Streptococcus dysgalactiae subsp. equisimilis Inhibits the Antimicrobial Peptide LL-37

DrsG from Streptococcus dysgalactiae subsp. equisimilis Inhibits the Antimicrobial Peptide LL-37

Growth Characteristics of and Virulence Factor Production by Group A Streptococcus during Cultivation in Human Saliva

Defensive Effects of Human Antimicrobial Peptide .ALPHA.-Defensins against Enterococcus faecalis

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