Scl1‐dependent internalization of group A Streptococcus via direct interactions with the α2β1 integrin enhances pathogen survival and re‐emergence

Caswell, Clayton C.; Lukomska, Ewa; Seo, Neung Seon; Höök, Magnus; Łukomski, Sławomir

doi:10.1111/j.1365-2958.2007.05741.x

Cited by 53 publications

(82 citation statements)

References 46 publications

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“…Thus, we determined the transcript levels of genes known to be directly regulated by Mga, including emm, scpA (encoding C5a peptidase), and sclA (encoding streptococcal collagenlike protein A). The C5a peptidase of GAS cleaves C5a, thereby inhibiting recruitment of phagocytic cells to the site of infection (45,46), whereas SclA is a cell surface protein involved in adherence and internalization (47). Consistent with our hypothesis, the transcripts of all Mga-regulated genes tested (emm, scpA, and sclA) were significantly decreased in strains MGAS12501 and MGAS12504 compared to MGAS315 (Fig.…”

Section: Resultssupporting

confidence: 77%

Natural Variation in the Promoter of the Gene Encoding the Mga Regulator Alters Host-Pathogen Interactions in Group A Streptococcus Carrier Strains

et al. 2013

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cHumans commonly carry pathogenic bacteria asymptomatically, but the molecular factors underlying microbial asymptomatic carriage are poorly understood. We previously reported that two epidemiologically unassociated serotype M3 group A Streptococcus (GAS) carrier strains had an identical 12-bp deletion in the promoter of the gene encoding Mga, a global positive gene regulator. Herein, we report on studies designed to test the hypothesis that the identified 12-bp deletion in the mga promoter alters GAS virulence, thereby potentially contributing to the asymptomatic carrier phenotype. Using allelic exchange, we introduced the variant promoter into a serotype M3 invasive strain and the wild-type promoter into an asymptomatic carrier strain. Compared to strains with the wild-type mga promoter, we discovered that strains containing the promoter with the 12-bp deletion produced significantly fewer mga and Mga-regulated gene transcripts. Consistent with decreased mga transcripts, strains containing the variant mga promoter were also significantly less virulent in in vivo and ex vivo models of GAS disease. Further, we provide evidence that the pleiotropic regulator protein CodY binds to the mga promoter and that the 12-bp deletion in the mga promoter reduces CodY-mediated mga transcription. We conclude that the naturally occurring 12-bp deletion in the mga promoter significantly alters the pathogen-host interaction of these asymptomatic carrier strains. Our findings provide new insight into the molecular basis of the carrier state of an important human pathogen.

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Section: Resultssupporting

confidence: 77%

Natural Variation in the Promoter of the Gene Encoding the Mga Regulator Alters Host-Pathogen Interactions in Group A Streptococcus Carrier Strains

et al. 2013

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“…Focal adhesion kinase (FAK); integrin-linked kinase (ILK); Rac; CDC42; and the Src kinases Src, Yes, and Fyn have also been shown to be involved in ␣5␤1-mediated GAS internalization (144,156). Similarly, the collagen-like protein Scl1 can also mediate epithelial cell adherence and internalization by directly binding to integrins ␣2␤1 and ␣11␤1 through their collagen-like domains (159,160). Once internalized, some GAS strains are susceptible to autophagy following escape from endosomes into the cytoplasm (161,162).…”

Section: Adherence Of Gasmentioning

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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“…1A). SclA contributes to GAS adherence and colonization through binding cellular fibronectin and laminin via the variable globular head (6) and integrins through the collagen-like region (7,8). Variability in the degree of binding between GAS serotypes to these and other host molecules is predicted based on the differences in the V and CL regions of SclA.…”

Section: T He Bacterial Pathogen Streptococcus Pyogenes (Group a Strementioning

confidence: 99%

Natural Variant of Collagen-Like Protein A in Serotype M3 Group A Streptococcus Increases Adherence and Decreases Invasive Potential

et al. 2015

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c Group A Streptococcus (GAS) predominantly exists as a colonizer of the human oropharynx that occasionally breaches epithelial barriers to cause invasive diseases. Despite the frequency of GAS carriage, few investigations into the contributory molecular mechanisms exist. To this end, we identified a naturally occurring polymorphism in the gene encoding the streptococcal collagen-like protein A (SclA) in GAS carrier strains. All previously sequenced invasive serotype M3 GAS possess a premature stop codon in the sclA gene truncating the protein. The carrier polymorphism is predicted to restore SclA function and was infrequently identified by targeted DNA sequencing in invasive strains of the same serotype. We demonstrate that a strain with the carrier sclA allele expressed a full-length SclA protein, while the strain with the invasive sclA allele expressed a truncated variant. An isoallelic mutant invasive strain with the carrier sclA allele exhibited decreased virulence in a mouse model of invasive disease and decreased multiplication in human blood. Further, the isoallelic invasive strain with the carrier sclA allele persisted in the mouse nasopharynx and had increased adherence to cultured epithelial cells. Repair of the premature stop codon in the invasive sclA allele restored the ability to bind the extracellular matrix proteins laminin and cellular fibronectin. These data demonstrate that a mutation in GAS carrier strains increases adherence and decreases virulence and suggest selection against increased adherence in GAS invasive isolates. T he bacterial pathogen Streptococcus pyogenes (group A Streptococcus [GAS]) causes a wide range of disease in humans. GAS causes severe invasive infections such as toxic shock syndrome and necrotizing fasciitis but is also the cause of milder, more benign infections (e.g., pharyngitis). In addition to causing disease, GAS colonizes the throats of humans in the absence of symptoms. Asymptomatic colonization rates range between 5 and 15% in healthy children (1), a rate that far exceeds that of GAS invasive disease (2). However, despite the high prevalence of GAS carriage, little is known about the molecular factors that contribute to asymptomatic colonization.Colonization of the host epithelium is a key first step to establishing GAS carriage or disease. GAS elaborates several key surface proteins that contribute to this process, including the M protein, fibronectin-binding proteins, the GAS pilus, and streptococcal collagen-like (Scl) proteins. The collagen-like protein SclA (also known as Scl1) is found in all GAS serotypes examined to date (3) and is positively regulated by the well-characterized regulator Mga (4). The SclA protein extends from the GAS cell surface in a homotrimeric, "lollipop-like" fashion (5). The outermost region consists of a globular head that varies considerably between GAS serotypes, followed by a repeating Gly-X-Y (GXY) collagen-like sequence that is in turn linked to the cell wall through a prolinerich linker region (see Fig. 1A). SclA contribu...

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Scl1‐dependent internalization of group A Streptococcus via direct interactions with the α₂β₁ integrin enhances pathogen survival and re‐emergence

Cited by 53 publications

References 46 publications

Natural Variation in the Promoter of the Gene Encoding the Mga Regulator Alters Host-Pathogen Interactions in Group A Streptococcus Carrier Strains

Natural Variation in the Promoter of the Gene Encoding the Mga Regulator Alters Host-Pathogen Interactions in Group A Streptococcus Carrier Strains

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Natural Variant of Collagen-Like Protein A in Serotype M3 Group A Streptococcus Increases Adherence and Decreases Invasive Potential

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