Regulation and function of the interleukin-8 cleaving cell envelope protease of Streptococcus pyogenes, SpyCEP. (360G-Wellcome-080091_Z_06_Z)

Gram positive bacteria secrete multi-domain subtilisin-like cell envelope proteinases (CEPs) linked to the bacterial cell surface. Originally believed relevant to nutrient acquisition alone, it is increasingly clear CEPs represent an novel family of Gram positive virulence factors which have evolved to specifically facilitate bacterial survival in humans. Translational research arising from comparison of patients who died or survived following necrotising fasciitis led us to investigate whether Streptococcus pyogenes interferes with the normal host chemotactic response. The novel S. pyogenes CEP (SpyCEP) was first identified in this laboratory as an enzyme that cleaves and inactivates human interleukin-8. Homologues exist in several other pathogens including S. agalactiae and S. pneumoniae, that are of known importance to virulence. Using SpyCEP as a model CEP, we will examine substrate range and factors which regulate production. Through genetic manipulation of bacteria, we will then investigate the specific role of CEPs in virulence using relevant models of infection. Building on the tools developed in the course of this study, we will explore the efficacy of SpyCEP vaccine strategies in invasive streptococcal disease and streptococcal carriage and investigate whether such an approach might have broad application in UK streptococcal disease.