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Title: Hyper-encapsulation and capsule regulation in Group A Streptococcus
Author: Lynskey, Nicola Nora
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Group A streptococcal (GAS) isolates of serotype M18 are widely known to exhibit a hyper-mucoid (highly-encapsulated) phenotype, but the mechanism behind the unusual colony morphology has never been elucidated. Whilst all serotypes of this important human pathogen produce differentia l amounts of the capsular polysaccharide M18 strains are unique. The M18 serotype is strongly associated with pharyngitis and the non-suppurative immune sequelae rheumatic fever, however the mechanism behind this disease association is unknown. This project set out to address the genetic mechanism by which capsule production is regulated in GAS and to determine the underlying cause of M18 mucoidy. Here we identify a novel and naturally-occurring serotype M18-specific truncation in the regulatory protein RocA, known to act on the streptococcal two-component regulatory system, CovR/S and demonstrate its role in a wider range of pathways by proteomic analysis. The serotype M18 RocA truncation is demonstrated to be both necessary and sufficient to induce the hyper-encapsulated phenotype characteristic of serotype M18 strains. Further, we demonstrate that reduction of capsule synthesis following replacement of truncated RocA with a full-length version of the protein abrogates capsule over-production and reverses the characteristic longevity of carriage associated with M18 strains. The M18 capsule is demonstrated to induce a pro-inflammatory response in vivo following colonisation, with relevance to the onset of rheumatic fever. Proteomic analysis highlights a potential role for RocA in metabolism homeostasis confirming the importance of this regulatory protein in Group A streptococcal virulence.
Supervisor: Sriskandan, Shiranee Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available