Date Published: July 4, 2013
Publisher: Public Library of Science
Author(s): Martina L. Sanderson-Smith, Yueling Zhang, Diane Ly, Deborah Donahue, Andrew Hollands, Victor Nizet, Marie Ranson, Victoria A. Ploplis, Mark J. Walker, Francis J. Castellino, Paul M. Sullam.
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.
An emerging theme in bacterial pathogenesis is sequestration of host plasminogen during disease initiation . This has inspired research to develop therapeutic inhibitors of bacterial plasminogen activation and recruitment , , , . To be successful, such strategies require a comprehensive understanding of how bacteria interact with the host fibrinolytic system. Group A streptococcus (GAS) is a globally significant human pathogen, responsible for 600,000 cases of invasive infection each year, approximately 25% of which are fatal . The ability of GAS to accumulate cell surface plasmin activity is an essential step in the initiation of invasive disease , , but the mechanistic basis of this virulence property has yet to be fully elucidated. While in vitro analyses suggest a role for host plasminogen activators in GAS disease , , , this hypothesis has yet to be conclusively demonstrated in vivo.
Despite increased research efforts over the past 20 years, GAS remains a significant human pathogen, with continued outbreaks of serious GAS infection globally . Interaction with the host protease plasmin is central to the onset of invasive GAS disease . A major consequence of plasmin acquisition in GAS infection is to facilitate bacterial escape from fibrin networks. uPA can facilitate efficient fibrin clearance in the absence of both uPAR and tPA , and the results of the current study provide for the first time, evidence that uPA mediated plasmin acquisition facilitates widespread systemic infection by GAS.