Unravelling the molecular mechanisms of invasive pneumococcal disease

Invasive pneumococcal disease causes over a million deaths per year worldwide, particularly in sub-Saharan Africa. Streptococcus pneumoniae strains vary considerably in virulence, but the reasons for this are unclear.

Capsular serotype 1 strains are particularly invasive and cause a major proportion of severe infections, including meningitis, but are poorly studied, partly because they have been genetically intractable.

We want to understand why serotype 1 strains are highly invasive, and to identify mechanisms that distinguish aggressive S. pneumoniae strains from less aggressive variants. Furthermore, a low-cost serotype 1 vaccine is urgently needed, especially in sub-Saharan Africa.

In this project, we will combine and exploit (i) recently-developed in vitro and in vivo infection models, (ii) bacterial RNAseq data (including our data obtained from cerebral spinal fluid from Malawian meningitis patients) and (iii) our methodologies for mutating serotype 1 strains, to identify and characterise the roles of multiple novel genetic determinants important for the pathogenesis of invasive S. pneumoniae infections.

We will also characterise in detail the zwitterionic capsular polysaccharide that defines serotype 1 strains and assess its role in pathogenesis.

Finally, we will exploit Protein Glycan Coupling Technology (pioneered by the applicants) to produce a much-needed and affordable glycoconjugate serotype 1 vaccine.