Streptococcal virulence and the coagulation system

Abstract: This thesis explores streptococcal virulence from both mechanistic and evolutionary perspectives, where the mechanistic studies focus on interactions with the human coagulation system. We describe interactions between streptococcal surface proteins and components of the intrinsic pathway of coagulation and the kallikrein-kinin system in human plasma, as well as to how these surface proteins are produced in different growth phases. The interactions involve activation of the kallikrein-kinin system and inhibition of its antibacterial effects. Inspired by these results, we review the literature, and develop a general model of streptococcal virulence. According to this model, the bacteria have two strategies, which we call asymptomatic colonization and superficial symptomatic infection, respectively, and they are adaptive under different epidemiological conditions. We propose that the bacteria's ability to cause invasive infections, which are the best studied, because they are the most severe, is a side effect of traits that evolved as adaptations for superficial symptomatic infections. This implies that many virulence mechanisms that have been described in invasive infections should have their functions in superficial symptomatic infections. We therefore investigate one such mechanism–the activation of host plasminogen–in conditions simulating pharyngitis, a very common superficial streptococcal infection. Pharyngitis is characterized by the exudation of plasma into an environment with saliva. We find that saliva affects the initiating enzymes of the intrinsic pathway of coagulation, and that this results in the formation of clots that entrap the bacteria. The bacteria escape the clots by activating host plasminogen, a finding that is in concordance with the model. As a whole this thesis underscores the utility of evolutionary analysis for interpreting and guiding mechanistic studies in infection biology, and conversely, the usefulness of mechanistic input for evolutionary theorizing.