Asymptomatic Carriage of Group A Streptococcus Is Associated with Elimination of Capsule Production

Flores, Anthony R.; Jewell, Brittany E.; Olsen, Randall J.; Shelburne, Samuel A.; Fittipaldi, Nahuel; Beres, Stephen B.; Musser, James M.

doi:10.1128/iai.01788-14

Cited by 43 publications

(56 citation statements)

References 56 publications

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“…3B). The finding of decreased bacterial burden in the mouse nasopharyngeal model is strikingly similar to that observed in GAS carrier strains deficient in capsule production (22).…”

Section: Resultssupporting

confidence: 64%

“…In an effort to identify key molecular genetic differences contributing to asymptomatic carriage of GAS, we performed wholegenome sequencing of 37 serotype M3 GAS isolates cultured serially from nine individuals over time (22). We discovered that four strains recovered from one subject contained a variant sclA allele compared to the reference serotype M3 genome.…”

Section: Resultsmentioning

confidence: 99%

“…Experiments assessing the ability to grow in human blood were conducted under a Houston Methodist Research Institute Institutional Review Board human subjects protocol and carried out as described previously (22,23). A minimum of two healthy, nonimmune, adult donors were used for each experiment.…”

Section: M3-flmentioning

confidence: 99%

“…Near mortality was determined by observation using predefined criteria for mice infected intramuscularly (21). Mouse nasopharyngeal colonization was performed as previously described (22). All mouse experiments were approved by the Institutional Animal Care and Use Committee of Houston Methodist Research Institute.…”

Section: M3-flmentioning

confidence: 99%

“…GAS adherence to cultured epithelial cells was carried out as previously described (22). Assays were performed in quadruplicate.…”

Section: M3-flmentioning

confidence: 99%

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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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“…3B). The finding of decreased bacterial burden in the mouse nasopharyngeal model is strikingly similar to that observed in GAS carrier strains deficient in capsule production (22).…”

Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: M3-flmentioning

confidence: 99%

Section: M3-flmentioning

confidence: 99%

“…GAS adherence to cultured epithelial cells was carried out as previously described (22). Assays were performed in quadruplicate.…”

Section: M3-flmentioning

confidence: 99%

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