Staphylococcus_aureus_populations_from_England. Staphylococcus_aureus_populations_from_England

Staphylococcus aureus is the second most common cause of bacteraemia in the UK, which still causes >20% mortality. The number of methicillin-sensitive S. aureus (MSSA) bacteraemia cases in England have increased by 39% over 9 years to 12,193 cases in 2019/20. The cause of the increase in MSSA bacteraemia cases in England over the last years is not apparent, but there is clear geographical variation across England, with the highest rates in the Northern and Southwestern England. As well as being a pathogen, S. aureus persistently colonises the nose in around 25% of the population, which increases the risk of S. aureus infection, including bacteraemia. No population level studies have been conducted in England (or elsewhere) to understand the population biology of colonising S. aureus, and how this relates and contrasts to the population causing bacteraemia. This is lack of data is particularly pertinent to current increase in MSSA bacteraemia in England, as we have no understanding if one or more epidemic clones has emerged and is causing the increasing number of cases. It is also unclear whether certain MSSA clones are more or less likely cause bacteraemia, and if distinct biological properties between clonal lineages enables them to colonise and cause disease in different ways. Particularly, we have little understanding of the role and interplay (epistasis) between core and accessory genome content, and role of more ancestral (e.g. deeper rooted – e.g. within a clonal complex) mutations have on determining the colonisation success and pathogenic potential of the distinct lineages of S. aureus. We are currently conducting two related population studies of Staphylococcus aureus focusing on the biological basis of colonisation (CARRIAGE study) and causes of increasing bacteraemia rates in England (AUREUS study – a collaboration with UK-HSA). The two studies will collect over 28,000 isolates (20K – CARRIAGE and 8K – AUREUS) collected over the same geographical areas and similar time periods. For both sets of isolates we hold detailed patient metadata (held at University of Cambridge and within UK-HSA). For the CARRIAGE study, we can link isolates to an individual’s host genetics (20K), nasal microbiome (~10K), various phenotypes (sizable subsets), lifestyle (all) and have established linkage to electronic health record data (all). This collection of isolates represents a uniquely deep sampling of S. aureus populations in both its primary niche, nasal colonisation, and in one of the most severe forms of staphylococcal disease, bacteraemia. I propose to whole genome sequence these isolates (total ~25,000 isolates in batches of 1000) and then using the sequencing data to: (1) Conduct a detailed genomic epidemiological analysis of S. aureus bacteraemia and carriage isolates from across England to determine population structure and temporal and geographical evolution, (2) To determine if a particular clone(s) and/or genetic trait is responsible for the increase in S. aureus bacteraemia in England (also reported in other countries), and the observed differences in geographical attack rates (this analysis will be conducted in collaboration with UK-HSA enabling a wide ranging epidemiological analysis including socioeconomic status), (3) To define the relative contribution of S. aureus genome content and mutation in colonising the human nares and causing bacteraemia, and to determine the mutational landscape and signatures of selection within each niche, including gene essentiality and the effect of an individual’s nasal microbiome content (e.g. the competitive environment), (4) To conduct the largest yet (by an order of magnitude) genome-wide association study of role of S. aureus genome content in determining bacteraemia risk and outcome of infection, (5) To identify any interaction between the genome of the colonising S. aureus strain - and an individual’s: (a) host genetics and lifestyle, and (b) nasal microbiome content. (6) To investigate the distinct genome content and biological characteristics of S. aureus clonal complexes to begin to understand evolutionary processes that have shaped the clonal structure of S. aureus population. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/