Defining capsule production by Staphylococcus aureus and the role it plays in patient outcome

Abstract

Staphylococcus aureus is one of the most important human pathogens, responsible for a wide variety of threatening illnesses. This pathogen's potential to cause infections is dependent on its numerous virulence factors as well as the rise in antibiotic resistance. The capsule is a crucial virulence component that aids the pathogen's survival within the host's immune system by evading phagocytosis. To better control S. aureus infections and identify innovative therapies, coordinated interdisciplinary methods must be used to understand pathogenesis. We screened 300 clinical isolates representing the two major clones that cause problems in UK and Irish hospitals, CC22 and CC30, for the production of the capsular polysaccharide (CP) and detected a significant variation in this activity. We identified several interesting associations with features such as methicillin resistance, mortality, and toxicity using statistical analysis, as well as novel AMR-related genes associated with CP synthesis. By utilising a genome-wide association study (GWAS) approach, we identified 170 loci that affected CP production. Two GWAS hits attracted our interest due to their association with the transformation of S. aureus into the small colony variant (SCV) or persister phenotype: menD and accA. Our findings suggest that menadione is required for the formation of the S. aureus capsule, and clinical isolates with SNPs in menD have increased gentamicin resistance but not the significant growth deficiency associated with the SCV phenotype. The accA gene, which encodes acetyl coenzyme A (acetyl-CoA) carboxylase, one of the first enzymes in the FASII pathway, also positively contributed to the production of capsule, associated with the triclosan-resistant SCV (tr-SCV) form. We also found the tr-SCV to be significantly attenuated in an insect model of infection due to a combination of it producing less capsules and toxins but also likely due to its slow growth rate.

Date of Award	28 Nov 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ruth C Massey (Supervisor) & Jim Spencer (Supervisor)