scholarly journals Role of Group A Streptococcal Virulence Factors in Adherence to Keratinocytes

2000 ◽  
Vol 68 (3) ◽  
pp. 1215-1221 ◽  
Author(s):  
Gary L. Darmstadt ◽  
Laurel Mentele ◽  
Andreas Podbielski ◽  
Craig E. Rubens
Keyword(s):  
Hyaluronic Acid ◽  
Mutant Strain ◽  
Virulence Factors ◽  
M Protein ◽  
Skin Infections ◽  
Wild Type ◽  
Group A ◽  
Hyaluronic Acid Capsule ◽  
Type Strains

ABSTRACT To evaluate the role of putative group A streptococcal virulence factors in the initiation of skin infections, we compared the adherence of a wild-type M49-protein skin-associated strain to that of a series of 16 isogenic mutants created by insertional inactivation of virulence genes. None of the mutants, including the M-protein-deficient (emm mutant) strain, displayed reduced adherence to early-passage cultured human keratinocytes, but adherence of the mutant lacking hyaluronic acid capsule expression (has mutant) was increased 13-fold. In contrast, elimination of capsule expression in M2-, M3-, and M18-protein has mutants increased adherence only slightly (1.3- to 2.3-fold) compared to their respective wild-type strains. A mutant with inactivation of both emm andhas displayed high-level adherence (34.9 ± 4.1%) equal to that of the has mutant strain (40.7 + 8.0%), confirming the lack of involvement of M49 protein in attachment. Moreover, adherence of the M49-protein-deficient (emmmutant) and wild-type strains was increased to the same level (57 and 55%, respectively) following enzymatic digestion of their hyaluronic acid capsule. Adherence of mutants lacking oligopeptide permease (Opp) expression was increased 3.8- to 5.5-fold, in association with decreased cell-associated hyaluronic acid capsule. Finally, soluble CD46 failed to inhibit adherence of M49- and M52-serotype skin strains. We conclude that (i) bacterial M protein and keratinocyte CD46 do not mediate adherence of M49 skin-associated Streptococcus pyogenes to epidermal keratinocytes, (ii) hyaluronic acid capsule impedes the interaction of bacterial adhesins with keratinocyte receptors, (iii) modulation of capsule expression may be important in the pathogenesis of skin infections, and (iv) the molecular interactions in attachment of skin strains of S. pyogenesto keratinocytes are unique and remain unidentified.

scholarly journals STUDIES ON THE PATHOGENICITY OF GROUP A STREPTOCOCCI

1959 ◽  
Vol 110 (4) ◽  
pp. 617-628 ◽  
Author(s):  
Marie Judith Foley ◽  
W. Barry Wood
Keyword(s):  
Hyaluronic Acid ◽  
Virulent Strain ◽  
Critical Role ◽  
M Protein ◽  
Group A Streptococci ◽  
Streptococcal Infections ◽  
Full Complement ◽  
Group A ◽  
Hyaluronic Acid Capsule

A quantitative study of the combined antiphagocytic effects of the M protein and the hyaluronic acid capsules of four strains of Group A streptococci revealed the following facts relating to their intraperitoneal virulence in mice and rats: 1. The most virulent strain, S23M (matt), produced both a large hyaluronic acid capsule and a full complement of M protein, the combined effects of which rendered the organism highly resistant to surface phagocytosis. 2. The slightly less virulent strain, T14/46 (matt virulent) was somewhat more susceptible to surface phagocytosis owing to the fact that its smaller capsule was less antiphagocytic than that of the S23M organism. 3. The glossy variant of the S23 strain (S23G), which ranked third in virulence, was still more susceptible to surface phagocytosis because of its lack of detectable M substance. Its large hyaluronic acid capsule, however, was capable of protecting it against phagocytosis on glass. 4. The least virulent strain, T14 (matt avirulent), was the most susceptible of all to phagocytosis. Though it possessed both M substance and capsule, which together prevented its phagocytosis on glass, each of them was shown to be quantitatively and functionally deficient as compared to Strain S23M. The differences in phagocytability, which appear to be directly related to the pathogenicity of the organisms, could be adequately demonstrated in vitro only by phagocytic tests designed to measure surface phagocytosis in the absence of opsonins. This fact is in keeping with the observation, previously reported, that surface phagocytosis plays a critical role in the defense of the host, particularly during the earliest stages of experimental streptococcal infections. Its possible relation to suppuration during the later stages of infection is also discussed.

scholarly journals Emergence of a New Highly Successful Acapsular Group A Streptococcus Clade of Genotype emm89 in the United Kingdom

mBio ◽  
2015 ◽  
Vol 6 (4) ◽  
Author(s):  
Claire E. Turner ◽  
James Abbott ◽  
Theresa Lamagni ◽  
Matthew T. G. Holden ◽  
Sophia David ◽  
...  
Keyword(s):  
United Kingdom ◽  
Hyaluronic Acid ◽  
Genome Sequencing ◽  
Virulence Factors ◽  
Invasive Disease ◽  
Whole Genome ◽  
The United Kingdom ◽  
Streptolysin O ◽  
Group A ◽  
Hyaluronic Acid Capsule

ABSTRACTGroup AStreptococcus(GAS) genotypeemm89 is increasingly recognized as a leading cause of disease worldwide, yet factors that underlie the success of thisemmtype are unknown. Surveillance identified a sustained nationwide increase inemm89 invasive GAS disease in the United Kingdom, prompting longitudinal investigation of this genotype. Whole-genome sequencing revealed a recent dramatic shift in theemm89 population with the emergence of a new clade that increased to dominance over previousemm89 variants. Temporal analysis indicated that the clade arose in the early 1990s but abruptly increased in prevalence in 2008, coinciding with an increased incidence ofemm89 infections. Although standard variable typing regions (emmsubtype,teetype,softype, and multilocus sequence typing [MLST]) remained unchanged, uniquely the emergent clade had undergone six distinct regions of homologous recombination across the genome compared to the rest of the sequencedemm89 population. Two of these regions affected known virulence factors, the hyaluronic acid capsule and the toxins NADase and streptolysin O. Unexpectedly, and in contrast to the rest of the sequencedemm89 population, the emergent clade-associated strains were genetically acapsular, rendering them unable to produce the hyaluronic acid capsule. The emergent clade-associated strains had also acquired an NADase/streptolysin O locus nearly identical to that found inemm12 and modernemm1 strains but different from the rest of the sequencedemm89 population. The emergent clade-associated strains had enhanced expression of NADase and streptolysin O. The genome remodeling in the new clade variant and the resultant altered phenotype appear to have conferred a selective advantage over otheremm89 variants and may explain the changes observed inemm89 GAS epidemiology.IMPORTANCESudden upsurges or epidemic waves are common features of group A streptococcal disease. Although the mechanisms behind such changes are largely unknown, they are often associated with an expansion of a single genotype within the population. Using whole-genome sequencing, we investigated a nationwide increase in invasive disease caused by the genotypeemm89 in the United Kingdom. We identified a new clade variant that had recently emerged in theemm89 population after having undergone several core genomic recombination-related changes, two of which affected known virulence factors. An unusual finding of the new variant was the loss of the hyaluronic acid capsule, previously thought to be essential for causing invasive disease. A further genomic adaptation in the NADase/streptolysin O locus resulted in enhanced production of these toxins. Recombination-related genome remodeling is clearly an important mechanism in group AStreptococcusthat can give rise to more successful and potentially more pathogenic variants.

M-protein gene-type distribution and hyaluronic acid capsule in group AStreptococcusclinical isolates in Chile: association ofemmgene markers withcsrRalleles

2011 ◽  
Vol 140 (7) ◽  
pp. 1286-1295 ◽  
Author(s):  
A. WOZNIAK ◽  
P. ROJAS ◽  
C. RODRÍGUEZ ◽  
A. UNDABARRENA ◽  
C. GARATE ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Virulence Factors ◽  
Protein Gene ◽  
Developed Countries ◽  
M Protein ◽  
Pacific Island ◽  
Non Invasive ◽  
Sterile Site ◽  
Hyaluronic Acid Capsule ◽  
The Relationship

SUMMARYStreptococcus pyogenescauses a variety of infections because of virulence factors such as capsular hyaluronic acid and M protein. The aim of this study was to determineemmtypes and capsule phenotype in 110 isolates ofS. pyogenesfrom patients with invasive (sterile sites) and non-invasive (mainly pharyngitis) infections in Chile, and the relationship between both virulence factors. The most abundant types found wereemm12,emm1,emm4andemm28and their distribution was similar to that seen in Latin America and developed countries, but very different from that in Asia and Pacific Island countries. Ten of 16emmtypes identified in pharyngeal isolates were found in sterile-site isolates, and three of nineemmtypes of sterile-site isolates occurred in pharyngeal isolates; threeemmsubtypes were novel. The amount of hyaluronic acid was significantly higher in sterile-site isolates but did not differ substantially amongemmtypes. Only three isolates were markedly capsulate and two of them had mutations in thecsrRgene that codes for a repressor of capsule synthesis genes. We found a non-random association betweenemmtypes andcsrRgene alleles suggesting that horizontal gene transfer is not freely occurring in the population.

scholarly journals Vitamin D and the Human Antimicrobial Peptide LL-37 Enhance Group A Streptococcus Resistance to Killing by Human Cells

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
John F. Love ◽  
Hien J. Tran-Winkler ◽  
Michael R. Wessels
Keyword(s):  
Vitamin D ◽  
Hyaluronic Acid ◽  
Antimicrobial Peptide ◽  
Virulence Factors ◽  
Regulatory System ◽  
Innate Immune ◽  
Invasive Infection ◽  
Streptolysin O ◽  
Group A ◽  
Hyaluronic Acid Capsule

ABSTRACTThe CsrRS two-component regulatory system of group AStreptococcus(GAS;Streptococcus pyogenes) responds to subinhibitory concentrations of the human antimicrobial peptide LL-37. LL-37 signaling through CsrRS results in upregulation of genes that direct synthesis of virulence factors, including the hyaluronic acid capsule and streptolysin O (SLO). Here, we demonstrate that a consequence of this response is augmented GAS resistance to killing by human oropharyngeal keratinocytes, neutrophils, and macrophages. LL-37-induced upregulation of SLO and hyaluronic acid capsule significantly reduced internalization of GAS by keratinocytes and phagocytic killing by neutrophils and macrophages. Because vitamin D induces LL-37 production by macrophages, we tested its effect on macrophage killing of GAS. In contrast to the reported enhancement of macrophage function in relation to other pathogens, treatment of macrophages with 1α,25-dihydroxy-vitamin D3 paradoxically reduced the ability of macrophages to control GAS infection. These observations demonstrate that LL-37 signals through CsrRS to induce a virulence phenotype in GAS characterized by heightened resistance to ingestion and killing by both epithelial cells and phagocytes. By inducing LL-37 production in macrophages, vitamin D may contribute to this paradoxical exacerbation of GAS infection.IMPORTANCEIt remains poorly understood why group AStreptococcus(GAS) causes asymptomatic colonization or localized throat inflammation in most individuals but rarely progresses to invasive infection. The human antimicrobial peptide LL-37, which is produced as part of the innate immune response to GAS infection, signals through the GAS CsrRS two-component regulatory system to upregulate expression of multiple virulence factors. This study reports that two CsrRS-regulated GAS virulence factors—streptolysin O and the hyaluronic acid capsule—are critical in LL-37-induced resistance of GAS to killing by human throat epithelial cells and by neutrophils and macrophages. Vitamin D, which increases LL-37 production in macrophages, has the paradoxical effect of increasing GAS resistance to macrophage-mediated killing. In this way, the human innate immune response may promote the transition from GAS colonization to invasive infection.

scholarly journals T4 Pili Promote Colonization and Immune Evasion Phenotypes of Nonencapsulated M4 Streptococcus pyogenes

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Yi-Hsuan Chen ◽  
Shao-Hui Li ◽  
Yao-Cheng Yang ◽  
Shu-Hao Hsu ◽  
Victor Nizet ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Epithelial Cells ◽  
Streptococcus Pyogenes ◽  
Whole Blood ◽  
Human Pathogen ◽  
Human Whole Blood ◽  
Epidemiologic Surveillance ◽  
Group A ◽  
Hyaluronic Acid Capsule

ABSTRACT Streptococcus pyogenes (group A Streptococcus [GAS]) is an important human pathogen causing a broad spectrum of diseases and associated with significant global morbidity and mortality. Almost all GAS isolates express a surface hyaluronic acid capsule, a virulence determinant that facilitates host colonization and impedes phagocyte killing. However, recent epidemiologic surveillance has reported a sustained increase in both mucosal and invasive infections caused by nonencapsulated GAS, which questions the indispensable role of hyaluronic acid capsule in GAS pathogenesis. In this study, we found that pilus of M4 GAS not only significantly promotes biofilm formation, adherence, and cytotoxicity to human upper respiratory tract epithelial cells and keratinocytes, but also promotes survival in human whole blood and increased virulence in murine models of invasive infection. T4 antigen, the pilus backbone protein of M4 GAS, binds haptoglobin, an abundant human acute-phase protein upregulated upon infection and inflammation, on the bacterial surface. Haptoglobin sequestration reduces the susceptibility of nonencapsulated M4 GAS to antimicrobial peptides released from activated neutrophils and platelets. Our results reveal a previously unappreciated virulence-promoting role of M4 GAS pili, in part mediated by co-opting the biology of haptoglobin to mitigate host antimicrobial defenses. IMPORTANCE Group A Streptococcus (GAS) is a strict human pathogen causing more than 700 million infections globally each year. The majority of the disease-causing GAS are encapsulated, which greatly guarantees survival and dissemination in the host. Emergence of the capsule-negative GAS, such as M4 GAS, in recent epidemiologic surveillance alarms the necessity to elucidate the virulence determinants of these pathogens. Here, we found that M4 pili play an important role in promoting M4 GAS adherence and cytotoxicity to human pharyngeal epithelial cells and keratinocytes. The same molecule also significantly enhanced M4 GAS survival and replication in human whole blood and experimental murine infection. T4 antigen, which composes the backbone of M4 pili, was able to sequester the very abundant serum protein haptoglobin to further confer M4 GAS resistance to antibacterial substances released by neutrophils and platelets.

scholarly journals Extracellular Cysteine Protease Produced by Streptococcus pyogenes Participates in the Pathogenesis of Invasive Skin Infection and Dissemination in Mice

1999 ◽  
Vol 67 (4) ◽  
pp. 1779-1788 ◽  
Author(s):  
Slawomir Lukomski ◽  
Charles A. Montgomery ◽  
Jacqueline Rurangirwa ◽  
Robert S. Geske ◽  
James P. Barrish ◽  
...  
Keyword(s):  
Mutant Strain ◽  
Cysteine Protease ◽  
Skin Infection ◽  
Immunogold Electron Microscopy ◽  
Wild Type ◽  
Systemic Dissemination ◽  
Group A ◽  
Protease Expression ◽  
Striking Contrast

ABSTRACT The role of an extracellular cysteine protease encoded by thespeB gene in group A Streptococcus (GAS) skin infection was studied with a mouse model. Mice were injected subcutaneously with a wild-type GAS serotype M3 strain or a cysteine protease-inactivated isogenic derivative grown to stationary phase. The mortality rate of mice injected with the M3 speB mutant strain was significantly decreased (P < 0.0008) compared to that of animals injected with the wild-type parental organism. The abscesses formed in animals infected with the cysteine protease mutant strain were significantly smaller (P< 0.0001) than those caused by the wild-type organism and slowly regressed over 3 to 4 weeks. In striking contrast, infection with the wild-type GAS isolate generated necrotic lesions, and in some animals the GAS disseminated widely from the injection site and produced extensive cutaneous damage. All of these animals developed bacteremia and died. GAS dissemination was accompanied by severe tissue and blood vessel necrosis. Cysteine protease expression in the infected tissue was identified by immunogold electron microscopy. These data demonstrate that cysteine protease expression contributes to soft tissue pathology, including necrosis, and is required for efficient systemic dissemination of the organism from the initial site of skin inoculation.

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