Year

2016

Degree Name

Doctor of Philosophy

Department

School of Biological Sciences

Abstract

Group A Streptococcus (GAS; group A streptococci; Streptococcus pyogenes) is a globally significant bacterial pathogen. The primary biological host for GAS is humans, and GAS is responsible for a plethora of non-invasive and invasive infections. Generally, GAS colonisation of superficial tissue sites, including the epidermal surface of the skin or the mucosal epithelium of the upper respiratory tract, results in non-invasive conditions such as impetigo and pharyngitis. Less commonly, GAS can gain access and disseminate into more sterile tissue areas. This leads to invasive life-threatening conditions, including necrotising fasciitis and streptococcal toxic shock syndrome, which involve destruction of the skin and soft tissue. Infection with GAS can also give rise to delayed nonsuppurative sequelae, such as rheumatic fever and acute glomerulonephritis, which are responsible for high rates of morbidity and mortality worldwide. The last comprehensive study assessing the global impact of diseases attributable to GAS estimated over 500,000 deaths per annum, placing this bacterium among the world’s most significant human pathogens. In the past few decades, there has been an increase in the severity and incidence of invasive GAS disease in Western countries, though currently it remains endemic in developing nations and Indigenous populations.

Subversion of the host plasminogen activation system is critical for streptococcal virulence. Central to this system is the blood-circulating zymogen plasminogen, that is activated to plasmin by host activators, urokinase plasminogen activator (uPA) or tissue plasminogen activator (tPA), as well as by bacterial activators, including the secreted GAS protein streptokinase. GAS recruits plasminogen to the bacterial cell surface via multiple cell surface receptors, and activation of bound plasminogen results in plasmin-coated GAS. Under physiological conditions, plasmin is strictly regulated by circulating inhibitors such as α2-antiplasmin, however under certain circumstances, plasmin localised at the GAS cell surface is protected from inhibition. Consequently, GAS can acquire an unregulated source of potent proteolytic activity at its cell surface, which is believed to facilitate the breakdown of host tissue barriers and extracellular matrix components (ECM). The human innate immune system serves as a protective shield against invading microbes during the early stages of infection. Plasmin-mediated immune evasion has recently emerged as a key mechanism in bacterial pathogenesis. In order to establish systemic infection, GAS must overcome the bactericidal effects of complement, a fundamental component of the innate immune response. A number of human pathogens have thwarted the complement system via either binding plasminogen directly to the cell surface or expressing plasminogen activators; both mechanisms result in proteolytic plasmin activity. Bacterial-generated plasmin has been shown to degrade essential components of the complement system, thereby preventing complement-driven phagocytosis, and enhancing the survival of the organism. However, there is limited knowledge on the impact of plasminogen activation and plasmin acquisition by GAS on host innate immunity. Furthermore, for a wide range of pathogenic microorganisms, surface bound plasminogen can be converted to plasmin by uPA and tPA, with the resulting plasmin activity facilitating host invasion by the bacterium. Streptokinase-generated plasmin activation has been thoroughly studied, however, the contribution of host activators to GAS pathogenesis has yet to be explored. To further clarify the role of the fibrinolytic system in GAS virulence, this project used two clinically important GAS isolates to investigate the impact of plasminogen activation and cell surface plasmin acquisition on the host innate immune response to GAS, and elucidate the contribution of uPA and tPA to invasive GAS disease.

FoR codes (2008)

0605 MICROBIOLOGY

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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.