title: 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.
authors.affiliation: Ilawarra Health and Medical Research Institute and School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia. martina@uow.edu.au
authors.forename: Martina L
authors.initials: ML
authors.lastname: Sanderson-Smith
authors.forename: Yueling
authors.initials: Y
authors.lastname: Zhang
authors.forename: Diane
authors.initials: D
authors.lastname: Ly
authors.forename: Deborah
authors.initials: D
authors.lastname: Donahue
authors.forename: Andrew
authors.initials: A
authors.lastname: Hollands
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Marie
authors.initials: M
authors.lastname: Ranson
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D060467:Disease Resistance; D004198:Disease Susceptibility; D004792:Enzyme Precursors / Q000097:blood / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D013290:Streptococcal Infections / Q000097:blood / Q000378:metabolism / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000378:metabolism* / Q000472:pathogenicity; D013300:Streptokinase / Q000378:metabolism; D013499:Surface Properties; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D004792:Enzyme Precursors; D010958:Plasminogen; D013300:Streptokinase; C049163:preprourokinase; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator