A specific type of streptococcal bacterium is increasingly causing brain abscesses in the UK, and researchers suspect that changes in its sugar-based outer coating are to blame. This matters because *Streptococcus intermedius* brain infections require neurosurgery and weeks of intravenous antibiotics, and kill about 10% of patients. The incidence of these infections is rising in several countries, yet no one knows why. The researchers have already identified distinct genetic variants of the capsule—the bacterium’s outer layer—and now want to test whether some variants make the bug better at invading the brain, resisting immune attack, or triggering damaging inflammation. If the work succeeds, it could explain the mysterious rise in these infections and identify which capsule types pose the greatest risk. That knowledge could eventually guide vaccine development or help clinicians target treatment more effectively. For now, the project is fundamental science: it aims to understand a basic biological mechanism—how capsule structure alters bacterial behaviour—rather than deliver an immediate clinical tool. Similar work on the related *Streptococcus pneumoniae* showed that capsular variation determines invasiveness, eventually leading to vaccines that prevent millions of infections.
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Streptococcus anginosus group infections, pyogenic infections of deep sterile sites, are increasing in the UK. Of the SAG species, Streptococcus intermedius is associated with particularly poor outcomes, with a predilection for brain infection, causing intracranial suppuration (ICS). These infections require neurosurgery, prolonged intravenous antibiotic treatment and cause a heavy burden of morbidity and mortality (10%). ICS is increasing in incidence in several countries including the UK; there is currently no explanation for this rise. We hypothesize that this increase is driven by increasing prevalence of more virulent S. intermedius strains, mediated by changes in its capsule. Capsule is a key streptococcal virulence factor. In S. pneumoniae, within the same Mitis clade as S. intermedius, capsular variation determines invasiveness and capacity to evade the immune response. S. intermedius expresses capsular polysaccharide, encoded by the cps locus. We have recently demonstrated the existence of distinct capsular genotypes in S. intermedius, expected to correlate with capsular structure. We hypothesize that capsular heterogeneity in S. intermedius, determined by cps genotype, alters strain virulence. Objectives of this work are to: 1. Characterize the impact of capsular genotype of S. intermedius on: (a) Invasive potential. (b) Resistance to opsonophagocytosis. (c) Innate immune inflammatory responses. 2. Develop competence-stimulating peptide (CSP) based mutagenesis approaches for S. intermedius to: (a) Generate isogenic capsular mutants to compare the impact of encapsulation for different cps genotypes on invasive potential and inflammatory responses (using the assays for aim 1). (b) Optimize the genetic approaches needed for future characterization of SAG virulence determinants.
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