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Title: Understanding the determinants of pathogenicity in Group A streptococcus
Author: Clarke, J.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Background: Streptococcus pyogenes is an important human pathogen responsible for clinical manifestations ranging from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The M surface protein encoded by the emm gene is used to type GAS isolates and is used as an epidemiological marker; over 230 emm types have been described to date. Using in vitro and in vivo models of GAS infection the aim of this thesis was to consider the different pathogenic mechanisms GAS employs to cause serious acute infection, host-immune evasion and chronic infection. Methods: In vitro characteristics such as susceptibility to opsonophagocytosis, complement deposition, and whole blood survival were characterised for a range of emm types across outbreak and non-outbreak isolates. These findings were translated to murine infection models of GAS. The role of streptolysin in determining disease outcome in vivo was investigated, by using two different clinical lineages: the emergent hypervirulent outbreak emm type 32.2 isolates including the development of an isogenic deletion mutant of streptolysin, that result in sepsis, and the emm type 1.0 isolates that cause septic arthritis. Finally, the local host immune response in the knee joints during arthritic GAS infection was characterised using flow cytometry and cytokine quantification. Results: The emm32.2 isolate was able to resist opsonophagocytosis, survive in whole blood, produce large quantities of highly haemolytic SLO and result in the rapid development of sepsis in the murine infection models. By contrast, the emm1.0 isolate was susceptible to opsonophagocytosis, was not able to survive in whole blood and produced lower levels of SLO which led to translocation of bacteria to the joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO also translocated to the joint, confirming the key role of SLO in determining infection niche. The characterisation of the immune response in the joint during infection showed a highly pro-inflammatory immune response with an influx of neutrophils, macrophages, and associated cytokines early in the infection which may ultimately contribute to the severe joint damage caused during GAS septic arthritis. Conclusion: The findings throughout this thesis have implications for the future of vaccine design and therapeutics for GAS. By understanding the mechanisms of infection, the varying virulence characteristics and the proceeding host response it provides a foundation with which to target specific bacterial and host proteins.
Supervisor: Kadioglu, Aras ; French, Neil ; Dean, Everett Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral