C5a peptidase (ScpA) is widely conserved amongst the streptococcal species, and plays a critical role in pathogenesis within the host. The only function of ScpA reported to date is the cleavage and inactivation of the complement anaphylatoxin C5a. Using complement deficient mice we established a novel complement-independent role for ScpA in promoting systemic infection, a phenotype we further characterised using a combination of in vitro assays and in vivo murine models.
Using Group A streptococcus as a model species, we generated isogenic ScpA knock-out strains in serotypes M1 and M89. ScpA promoted bacterial resistance to clearance early during infection in a murine soft-tissue infection model in both wildtype mice and those lacking complement component C5. Unexpectedly ScpA also promoted systemic dissemination via the bloodstream in mice lacking both C3 and C5. We went on to characterise ScpA as an adhesin, sufficient to mediate bacterial attachment to human epithelial cells and both human and murine endothelial cells, and conclude that this function is critical for streptococcal virulence in vivo. We also report complement components C3a and C3 as novel substrates for ScpA, cleavage of which resulted in functional inactivation of both proteins, impairing the innate immune response by inhibition of C3 deposition on the bacterial surface, and effective neutrophil activation and function.
Taken together we demonstrate that during infection ScpA promotes streptococcal pathogenesis via multiple complement independent and dependent mechanisms, which collectively dramatically impair host immune control during infection.