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Group A streptococcal necrotising fasciitis and its association with blunt trauma

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Lucy Lamb FINAL thesis Nov 2015.pdfThesis100.86 MBAdobe PDFView/Open
Title: Group A streptococcal necrotising fasciitis and its association with blunt trauma
Authors: Lamb, Lucy Elizabeth Moffatt
Item Type: Thesis or dissertation
Abstract: Necrotising fasciitis (NF) due to invasive Group A streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of approximately 40%. Cases occur in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion and no obvious portal of entry. Using a new model of mild contusion injury, we set out to determine the impact of contusion on iGAS bacterial burden, phenotype and host cytokine response. Firstly invasive bioluminescent GAS strains were developed using a replicative plasmid pTHLK but these were unstable in vivo. A stably bioluminescent M89 iGAS strain was developed using a plasmid pICL18Lux and characterised in vitro and in vivo models of invasive infection. Bioluminescence measured in vivo correlated with bacterial quantity but practical application to produce a lower respiratory tract infection or prolonged soft tissue infection was limited by detection of light production during infection. The new isolate was attenuated in growth and virulence and it could not be used to study the interaction of contusion and virulence. A new model of soft tissue contusion was developed that resulted in local soft tissue neutrophilic inflammation, no bony injury, systemic cytokine production or weight loss. The model of mild contusion was used to determine the impact of trauma on emm1 iGAS. Surprisingly, mild contusion did not provide a focus for initiation or seeding of bacteraemic GAS infection, but instead provided an environment that enhanced GAS dissemination to local lymph nodes. Dissemination was linked to a phenotypic change with the emergence of mucoid GAS colonies in lymphoid tissue, bloodstream and spleen. The mucoid GAS colonies in the lymph node demonstrated a significant increase in production of capsular hyaluronan and were not associated with covRS mutations. Whole genome sequencing was applied to understand the genetic change responsible, a selection of mutations occurring in the spleen and lymph node were discovered. The exact role of some of the mutations in the pathogenesis of dissemination of GAS and the influence of trauma is not entirely known and the subject of on-going investigation.
Content Version: Open Access
Issue Date: Jun-2015
Date Awarded: Dec-2015
URI: http://hdl.handle.net/10044/1/55260
DOI: https://doi.org/10.25560/55260
Supervisor: Sriskandan, Shiranee
Sponsor/Funder: Ministry of Defence
Funder's Grant Number: P33625
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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