Understanding and exploiting Group A streptococcal anti-chemotactic proteases in vaccines for infection

Streptococcus pyogenes is a major human pathogen responsible for a significant global disease burden. Despite a century of research, there is no effective vaccine, in part due to the existence of multiple serotypes that vary worldwide. Notably, S. pyogenes produces two surface-associated serine proteases that inactivate specific neutrophil chemotactic signalling families. SpyCEP cleaves and inactivates the entire family of neutrophil-active CXC-chemokines including IL8/CXCL8, while C5a peptidase (ScpA) cleaves and inactivates both C5a and C3a. Both SpyCEP and ScpA are major, yet fully conserved, targets in the protective human antibody response against S. pyogenes and are therefore leading candidate vaccine targets. There is, however, minimal structural information to indicate how these proteases function to recognise or cleave their substrates, nor factors that influence activity. We will undertake - Comprehensive evaluation of the structures of each enzyme complexed with substrate - Detailed examination of enzymology and substrate specificity - Systematic study of the expression and role of the enzymes in vivo - Use the above data to develop and design hybrid vaccine antigens to evaluate in vivo Such information would greatly advance our fundamental understanding about this family of enzymes, providing a platform for novel vaccine antigen design, and future opportunities for drug development.