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Non-travel associated Salmonella Typhimurium ST 313 in the UK Philip Ashton, Satheesh Nair, Chris Lane, Elizabeth de Pinna, Tansy Peters, Kathie Grant, Tim Dallman Gastrointestainal Bacteria Reference Unit, Public Health England, 61 Colindale Avenue, NW9 5DZ INTRODUCTION PHE strains Salmonella enterica serovar Typhimurium typically causes self-limiting gastroenteritis. However, invasive non-typhoidal Salmonella disease has been recently documented in many sub-Saharan African countries, causing significant morbidity and mortality. The majority of these invasive isolates belong to one of two monomorphic lineages within a single MultiLocus-Sequence-Type, ST313. There is also evidence that ST313 is more invasive than other closely related S. Typhiumrium in both humans (clinical reports) and chickens (in vivo experiments). Here, we present an analysis of ST313 isolates received by the PHE Salmonella Reference Service. Patient Year of isolation Phage type Travel Sample type R-type Patient 1 2012 RDNC None reported Faeces SUL/NAL/CIP0.125 Patient 2 2012 RDNC None reported Faeces Sensitive Patient 3 2012 DT 56 Ghana Blood isolate AMP/CHL/STR/SUL/T MP/NAL/CIP0.125 Patient 4 2012 DT 2 None reported Faeces Sensitive Patient 5 2012 RDNC None reported Faeces Sensitive Patient 6 2012 DT 143 None reported Faeces Sensitive Patient 7 2012 DT 75 None reported Faeces Sensitive Blood/bronchial isolates AMP/CHL/SUL/STR/T MP Patient 8 2014 DT 56 None reported - not on NHS system Patient 9 2014 DT 143 None reported Faeces Sensitive Patient 10 2014 ND None reported Faeces - Patient 11 2014 DT 132 None reported ND Sensitive Patient 12 2014 DT 132 None reported Faeces Sensitive Patient 13 2014 DT 103 None reported Faeces Sensitive Patient 14 2014 DT 15a None reported ND Sensitive Patient 15 2014 DT 56 Nigeria Blood isolate AMP/CHL/SUL/STR/T MP Patient 16 2014 DT 2 None reported Blood isolate Sensitive Lineage II II II Table 1: S. Typhimurium ST313 isolates received by the PHE Salmonella Reference Service. RESULTS Within the wider phylogenetic context of S. Typhimurium, ST313 isolates submitted to PHE formed a monophyletic group with the African ST313 isolates described previously. The most recent common ancestor (MRCA) of all ST313 dates to 1810 (95% highest posterior distribution, 1742-1869). Descending from this ancestor are 6 lineages of ST313, 5 of which had representatives referred to SRS between 2012 and 2014. ST313 isolated from Africa are typically multi-drug resistant (MDR), with resistance driven by a plasmid borne MDR locus. This entire set of loci was missing from the non-lineage I/II isolates. The BTP-1 phage, which is identical between lineage I and II, is a site of signficicant variability among non-lineage I/II isolates. All ST313 have a disrupted BTP1 insertion site, even those where the BTP-1 phage is not present. This is the first description of a BTP-1 like phage in ST19. The ST19 strain in which it was identified is the closest ST19 ancestor of ST313 among our sequenced strains. Figure 1: BEAST tree of ST313 from PHE and Okoro et al., 2012. Previously identified lineages I & II are annotated. Node labels are posterior probabilities and node bars are 95% higher probability distributions of the node height. Methods cont. Discussion Twenty three representative ST313 sequenced by Okoro et al., were downloaded from the NCBI Short Read Archive. The data we present here indicates that ST313 in the UK is epidemiologically, clinically and genomically, heterogenous All sequencing data (PHE & Sanger Centre) was quality trimmed using Trimmomatic, mapped against the LT2 reference genome (AE006468) using BWA mem. SNPs were then called using GATK2 Core genome positions that had a high quality SNP (>90% consensus, minimum depth 10x, GQ >= 30, MQ >=30) in at least one strain were extracted and RAxML v7.2.8 with the gamma model of rate heterogeneity and 100 bootstraps carried out To examine the evolutionary history of ST313, a number of timed phylogenies were constructed using BEAST v1.8.0, with varying clock rate models and tree priors. The resulting models were compared and the one that best fit the data was a log normal relaxed clock rate with an exponential growth tree prior. There are the travel associated ST313 (3/16 patients), which fall within the previously described lineage II. These isolates are invasive (3/3 patients bacteraemic) and are multi-drug resistant, encoding the same antibiotic resistance determinants as previously described lineage II isolates (Okoro et al. 2012). There are also non-travel associated ST313 (13/16, 5 of whom were subjected to extended questionnaires). Of these 13 isolates, only one was associated with invasive disease and one isolate was phenotypically resistant to any of the antibiotics tested There are accessory genome differences between the lineage I/II ST313 and the non-lineage I/II ST313. Long read sequencing would help to clarify this picture. Figure. The presence of BTP-1 in ST313 ACKNOWLEDGEMENTS We would like to acknowledge PHE’s Genome Sequencing and Development Unit and Infectious Disease Informatics, Martin Day for antimicrobial resistance typing. We would also like to thank Jay Hinton and Sian Owen for helpful discussions and comments. REFERENCES Okoro, C.K. et al., 2012. Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa. Nature genetics, (September), pp.1–9. Feasey, N. a et al., 2012. Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa. Lancet, 379(9835), pp.2489–99. Kingsley, R. a et al., 2009. Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome research, 19(12), pp.2279–87. Parsons, B.N. et al., 2013. Invasive non-typhoidal Salmonella typhimurium ST313 are not host-restricted and have an invasive phenotype in experimentally infected chickens. PLoS neglected tropical diseases, 7(10), p.e2487