Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Walker, Mark J.; Barnett, Timothy C.; McArthur, Jason D.; Cole, Jason N.; Gillen, Christine M.; Henningham, Anna; Sriprakash, Kadaba S.; Sanderson-Smith, Martina L.; Nizet, Victor

doi:10.1128/cmr.00101-13

Cited by 685 publications

(720 citation statements)

References 599 publications

(631 reference statements)

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“…coiled coil | group A Streptococcus | M protein | fibrinogen | dynamics M proteins are the major surface-associated virulence factors of group A Streptococcus (GAS; Streptococcus pyogenes) and play a significant role in the diverse diseases caused by this widespread bacterial pathogen (1)(2)(3). M protein sequences are antigenically variable but have in common a strong propensity to form α-helical coiled coils (4).…”

mentioning

confidence: 99%

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Stewart

Buffalo

Valderrama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The sequences of M proteins, the major surface-associated virulence factors of the widespread bacterial pathogen group A Streptococcus, are antigenically variable but have in common a strong propensity to form coiled coils. Paradoxically, these sequences are also replete with coiled-coil destabilizing residues. These features are evident in the irregular coiled-coil structure and thermal instability of M proteins. We present an explanation for this paradox through studies of the B repeats of the medically important M1 protein. The B repeats are required for interaction of M1 with fibrinogen (Fg) and consequent proinflammatory activation. The B repeats sample multiple conformations, including intrinsically disordered, dissociated, as well as two alternate coiled-coil conformations: a Fg-nonbinding register 1 and a Fg-binding register 2. Stabilization of M1 in the Fg-nonbinding register 1 resulted in attenuation of Fg binding as expected, but counterintuitively, so did stabilization in the Fg-binding register 2. Strikingly, these register-stabilized M1 proteins gained the ability to bind Fg when they were destabilized by a chaotrope. These results indicate that M1 stability is antithetical to Fg interaction and that M1 conformational dynamics, as specified by destabilizing residues, are essential for interaction. A "capture-and-collapse" model of association accounts for these observations, in which M1 captures Fg through a dynamic conformation and then collapses into a register 2-coiled coil as a result of stabilization provided by binding energy. Our results support the general conclusion that destabilizing residues are evolutionarily conserved in M proteins to enable functional interactions necessary for pathogenesis.M proteins are the major surface-associated virulence factors of group A Streptococcus (GAS; Streptococcus pyogenes) and play a significant role in the diverse diseases caused by this widespread bacterial pathogen (1-3). M protein sequences are antigenically variable but have in common a strong propensity to form α-helical coiled coils (4). Paradoxically, these sequences are also replete with residues that destabilize coiled coils (5, 6). These destabilizing residues occur at the central a and d positions of the coiled-coil [abcdefg] n heptad repeat (Fig. 1). For dimeric α-helical coiled coils, as is the case for M proteins (7-9), the a and d positions are preferentially occupied by Val and Leu, respectively (10, 11). These small, hydrophobic residues typically engage in "knobs-into-hole" packing and form the hydrophobic core of the coiled-coil dimer. In contrast, the a and d positions of M proteins are often occupied by coiled-coil destabilizing residues (e.g., charged residues or alanines), and the heptad pattern sometimes contains short insertions or deletions (Fig. 1B) (5, 9). These sorts of destabilizing residues and heptad disruptions result in a highly irregular coiled-coil structure in M1 protein (9). The high proportion of coiled-coil destabilizing residues is also consistent with M protei...

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confidence: 99%

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Stewart

Buffalo

Valderrama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…One of the most-studied two component GAS regulatory systems is CovRS, which is responsible for regulating 10–15% of the GAS genome, and repressing the expression of virulence genes such as those of the hasABC operon that result in expression of hyaluronan capsule [8]. CovRS plays an important role in the systemic dissemination of GAS and spontaneous mutations have been demonstrated in hyper-encapsulated emm 1 GAS isolates from spleen during experimental in vivo infection [9,10].…”

Section: Introductionmentioning

confidence: 99%

Impact of contusion injury on intramuscular emm1 group a streptococcus infection and lymphatic spread

Siggins

Scudamore

et al. 2018

Virulence

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Invasive group A Streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of around 20%. Cases occasionally arise in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new murine model of contusion, we determined the impact of contusion on iGAS bacterial burden and phenotype.Calibrated mild blunt contusion did not provide a focus for initiation or seeding of GAS that was detectable following systemic GAS bacteremia, but instead enhanced GAS migration to the local draining lymph node following GAS inoculation at the same time and site of contusion. Increased migration to lymph node was associated with emergence of mucoid bacteria, although was not specific to mucoid bacteria. In one study, mucoid colonies demonstrated a significant increase in capsular hyaluronan that was not linked to a covRS or rocA mutation, but to a deletion in the promoter of the capsule synthesis locus, hasABC, resulting in a strain with increased fitness for lymph node migration.In summary, in the mild contusion model used, we could not detect seeding of muscle by GAS. Contusion promoted bacterial transit to the local lymph node. The consequences of contusion-associated bacterial lymphatic migration may vary depending on the pathogen and virulence traits selected.

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“…Los factores de riesgo asociados con el estado de portador pueden ser la hipertrofia adenofaríngea (9), ser niño, portar los tipos emm 1, 3, 12 y 28 (10) y ser trabajador de la salud (11). Las consecuencias de ser portador asintomático no están del todo claras, pero los sujetos pueden ser fuentes potenciales de brotes infecciosos o de autoinoculación en heridas de la piel (10). Es por ello que la determinación del estado de portador puede resultar importante en los contextos donde persistan dichos factores de riesgo; sin embargo, no se ha determinado si esta situación puede ser detectada con facilidad por los métodos diagnósticos tradicionales.…”

Section: Introductionunclassified

Detección de la colonización asintomática en orofaringe por Streptococcus pyogenes mediante dos métodos diagnósticos

Vasco

Luna

2017

Rev. Fac. Med.

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Detección de la colonización asintomática en orofaringe porStreptococcus pyogenes mediante dos métodos diagnósticos Objetivo. Determinar la presencia de estudiantes de medicina en estado de portador de S. pyogenes mediante dos métodos diagnósticos. Materiales y métodos.Se realizó un estudio de corte transversal con muestreo por conveniencia donde se analizaron muestras de orofaringe por inmunoensayo enzimático StrepA y cultivo bacteriano en agar base sangre de cordero al 5% más pruebas diferenciales con el objetivo de detectar la presencia de S. pyogenes. Resultados.De 77 muestras incluidas en el análisis, 3 (3.9%) fueron positivas por el cultivo microbiológico para S. pyogenes y ninguna por el método StrepA.Conclusión. El hallazgo de la bacteria S. pyogenes entre los estudiantes de medicina asintomáticos alerta de un potencial infeccioso. En la comparación de los métodos diagnósticos para su detección, los hallazgos validan el uso del cultivo sobre el del StrepA, en el caso de que se desee estimar la presencia de portadores de dicho agente.

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Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Cited by 685 publications

References 599 publications

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction

Impact of contusion injury on intramuscular emm1 group a streptococcus infection and lymphatic spread

Detección de la colonización asintomática en orofaringe por Streptococcus pyogenes mediante dos métodos diagnósticos

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