Plasminogen Is a Critical Host Pathogenicity Factor for Group A Streptococcal Infection.
Authors: Sun Hongmin , Ringdahl Ulrika , Homeister Jonathon W. , Fay William P. , Engleberg N. Cary , Yang Angela Y. , Rozek Laura S. , Wang Xixi , Sjobring Ulf , Ginsburg David 
Published: October 2019

Group A streptococci (GAS), a common human pathogen, secrete streptokinase (SK), which activates the host’s blood clot-dissolving protein, plasminogen (PLG). SK is highly specific for human PLG, exhibiting little or no activity against other mammalian species, including mouse. In addition to the species specificity of SK interaction with host PLG, species specificity has also been demonstrated for PLG receptors on the bacterial surface, such as the bacterial surface protein, PAM, and for interactions with fibrinogen. We generated a “humanized” transgenic mouse expressing human PLG under control of the mouse albumin gene regulatory sequences within a Bacteria Artificial Chromosome (BAC) transgene. The highest expressing transgenic founder line produced human PLG corresponding to ~17% of the PLG level in control human plasma (16.7±1.78) and largely rescued the prothromobtic morbidity otherwise observed in Plg null mice. Mice are generally highly resistant to subcutaneous infection by most human pathogenic GAS. However, introduction of human PLG expressed by the transgene markedly increased mortality to 75% from 20% in Tg− littermate control using the GAS strain 2616, exhibiting enhanced virulence due to site-directed mutation in the regulatory locus, csrRS. Similar differences in mortality were also observed with a wildtype GAS strain. The increased susceptibility of Tg+ mice to GAS was largely abrogated by deletion of the SK gene, demonstrating the major role of the PLG/SK interaction in GAS pathogenicity. Marked differences in mortality were also observed in Tg+ mice infected by the PAM expressing GAS strain AP53 and its PAM− isogenic variant, demonstrating a role for PAM in focusing PLG at the bacterial surface. We hypothesize that GAS hijack the host fibrinolytic system in order to circumvent local thrombosis and microvascular occlusion and reopen the vascular tree to systemic spread. Consistent with this model, the marked difference in mortality between Tg+ and Tg− mice was no longer observed when GAS were injected directly intravenously. In addition, a significant increase in bacterial colonies in the spleens of Tg+ mice was observed following subcutaneous GAS injection. Markedly increased mortality was also observed following GAS injection in C57BL/6J mice treated with the snake venom Ancrod, which proteolytically degrades plasma fibrinogen, consistent with a key role for fibrin deposition in host defense against GAS dissemination. In summary, activation of host plasminogen by SK leads to accelerated clearance of host fibrin and is a central mechanism for GAS invasion and spread. It is likely that similar interactions are central to the invasive program of other unrelated PA-associated pathogens that occupy diverse microenvironmental niches. The remarkable species specificity of SK for host PLG probably resulted from host and pathogen coevolution. These observations highlight the potential role of infectious disease as a critical force in the evolution of the hemostatic system and the unusual species specificity of many coagulation factor interactions.