Pathogenesis and Prevention of Pneumococcal Disease

Investigators: Prof. James Paton, Dr. David Ogunniyi, Dr. Uwe Stroeher, Dr. Judy Morona, Dr. Tony Focareta

Streptococcus pneumoniae (the pneumococcus) is a major human respiratory pathogen, causing as many deaths in young children as all bacterial enteric pathogens combined. Global management of pneumococcal disease is complicated by an alarming increase in the prevalence of pneumococci resistant to multiple antibiotics, and the poor clinical efficacy of existing vaccines. This programme has the broad aim of gaining a complete understanding of the molecular mechanism whereby S. pneumoniae invades and damages body tissues, with a view to improving preventative and therapeutic strategies against pneumococcal disease. Experimental approaches include identification and characterization of candidate virulence factors, construction of derivatives of S. pneumoniae with defined mutations in the genes which encode them, and examining the impact on virulence in a mouse model. Other studies involve examination of in vivo alterations in expression of putative virulence factor genes. This information is being used to design and test novel pneumococcal vaccines based on combinations of virulence proteins. Such combination protein vaccines are likely to provide broader protection than the recently released serotype-specific polysaccharide-protein conjugate vaccines. Moreover, they will be vastly cheaper to produce, thereby enabling deployment in third world countries, where the need for effective pneumococcal vaccines is greatest.

We are also conducting a thorough molecular genetic investigation of the S. pneumoniae polysaccharide capsule, which is a sine qua non of pneumococcal virulence. Each of the 90 pneumococcal serotypes produces a structurally distinct capsular polysaccharide (CPS). Until recently, however, very little was known of the genes controlling biosynthesis and expression of this most important family of surface antigens, or how the pneumococcus acquired the capacity to synthesise such a vast array of capsular serotypes. Sequence analysis of several serotypes indicates that these loci are complex, containing up to 20 genes, which appear to be arranged as single transcriptional units. Phenotypic characterization of pneumococci carrying mutagenized cps genes, comparisons with sequence databases and complementation analysis is enabling us to determine the function of the various gene products, as well as biosynthetic pathways for the respective CPS. Knowledge of the factors determining or regulating capsular expression is likely to provide new insights into the pathogenesis of pneumococcal disease, and shed light on the mechanism for generation of capsular diversity in pneumococci. Importantly, these studies may also identify alternative targets for vaccines or antimicrobial therapy.