Year

2011

Degree Name

Doctor of Philosophy

Department

School of Biological Sciences

Abstract

Streptococcus pyogenes (group A streptococcus; GAS) causes ~700 million human infections each year, resulting in over 500,000 deaths. GAS can cause mild infections such as pharyngitis and impetigo, in addition to life threatening conditions including necrotising fasciitis, streptococcal toxic shock syndrome (STSS) and bacteremia. Repeated infection with GAS may result in the non-suppurative sequelae, acute rheumatic fever (ARF) and acute glomerulonephritis (APSGN). GAS remains sensitive to the antibiotic penicillin which can be administered as a means to treat infection or as prophylaxis. This strategy is utilised in regions with high GAS endemicity such as Indigenous populations living in northern Australia who suffer some of the highest rates of GAS auto-immune sequelae worldwide. However, issues with patient compliance and a growing concern over the possible emergence of resistant GAS strains may limit the usefulness of penicillin in the future. A vaccine capable of preventing GAS infection may be the only effective way to control and eliminate GAS infection and disease.

The development of a commercial GAS vaccine is hampered by the occurrence of many unique GAS serotypes, antigenic variation within the same serotype, differences in geographical distribution of serotypes and the production of antibodies cross-reactive with human tissue that may lead to auto-immune disease. Several independent studies have documented a number of GAS cell wall-associated or secreted metabolic enzymes which contain neither N-terminal leader sequences nor C-terminal cell wall anchors. A proteomic analysis of serotype M1T1 GAS cell wall extracts was undertaken for the purpose of vaccine development. This approach catalogued 13 novel anchorless proteins and following a series of characterisation experiments identified two protective vaccine candidates, arginine deiminase (ADI) and trigger factor (TF). ADI and TF conferred protective efficacy in two murine models of GAS infection; systemic and subcutaneous. These surface-exposed antigens are expressed across multiple GAS serotypes exhibiting ≥ 99% amino acid sequence identity. Vaccine safety concerns are alleviated by the observation that these vaccine candidates lack human homologs, while sera from human populations suffering repeated GAS infections and high levels of auto-immune complications do not recognise these enzymes. In addition, anti-sera raised against ADI and TF does not react with human heart extract. Both ADI and TF warrant further investigation as GAS vaccine candidates for the prevention of GAS disease, which despite many decades of research trying to find a suitable vaccine, remains a major cause of morbidity and mortality worldwide.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.