A Key Role for the Urokinase Plasminogen Activator (uPA) in Invasive Group A Streptococcal Infection

Abstract

Recruitment of the serine protease plasmin is central to the pathogenesis of many bacterial species, including Group A streptococcus (GAS), a leading cause of morbidity and mortality globally. A key process in invasive GAS disease is the ability to accumulate plasmin at the cell surface, however the role of host activators of plasminogen in this process is poorly understood. Here, we demonstrate for the first time that the urokinase-type plasminogen activator (uPA) contributes to plasmin recruitment and subsequent invasive disease initiation in vivo. In the absence of a source of host plasminogen activators, streptokinase (Ska) was required to facilitate cell surface plasmin acquisition by GAS. However, in the absence of Ska, host activators were sufficient to promote cell surface plasmin acquisition by GAS strain 5448 during incubation with plasminogen or human plasma. Furthermore, GAS were able mediate a significant increase in the activation of zymogen pro-uPA in human plasma. In order to assess the contribution of uPA to invasive GAS disease, a previously undescribed transgenic mouse model of infection was employed. Both C57/black 6J, and AlbPLG1 mice expressing the human plasminogen transgene, were significantly more susceptible to invasive GAS disease than uPA−/− mice. The observed decrease in virulence in uPA−/−mice was found to correlate directly with a decrease in bacterial dissemination and reduced cell surface plasmin accumulation by GAS. These findings have significant implications for our understanding of GAS pathogenesis, and research aimed at therapeutic targeting of plasminogen activation in invasive bacterial infections.

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…Thus, covRS mutations enhance the ability of an isolate to activate plasminogen (255). In addition, it has recently been demonstrated that serotype M1T1 GAS strains utilize the host activator uPA to acquire cell surface plasmin in the absence of Ska and that this interaction also plays a role in a mouse model of invasive GAS disease (335).…”

Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications

“…It has been shown that the components of the uPA system are expressed in various types of hemopoietic cells ( 78 ). More importantly, their levels are altered during the course of infections suggesting the role of the uPA–uPAR system in mediating different types of immune response ( 87 – 89 ). In response to bacterial infection, proinflammatory cytokines such as TNF-α and IL-1β are released, which in turn increases uPA expression and secretion by different types of monocytes, neutrophils, epithelial and endothelial cells ( 87 ).…”

A critical role for plasminogen in inflammation

“…For example, the gram-negative bacteria Moraxella catarrhalis and Pseudomonas aeruginosa , as well as spirocytic bacteria Borrelia crocidurae and Borrelia burgdorferi , each bind plasminogen for host invasion (Singh et al, 2015; Ceremuga et al, 2014; Nordstrand et al, 2001; Gebbia et al, 1999; Coleman et al, 1995). In addition, gram-positive bacteria, such as Streptococcus pneumoniae , bind plasminogen and uPA to induce plasmin recruitment and initiation of bacterial invasion into the host while evading the normal innate immune response (Agarwal et al, 2013; Sanderson-Smith et al, 2013). Staphylococcus aureus , a gram-positive bacteria that causes infection of the skin and soft tissues, encodes its own plasminogen activator, staphylokinase, which induces plasmin activity and aids in invasiveness of S. aureus , inducing larger lesions in the host and decreased ability of the host to clear the bacteria (Peetermans et al, 2014).…”