Acknowledgements: We are grateful to Jacqueline Keane, Christoph Puethe and the Pathogen Informatics team (Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom) for the support. The work by S.V.P. and G.D. is funded in part by a grant from the Bill & Melinda Gates Foundation (OPP1151153). R.K. and M.B. were supported by research grants BB/N007964/1 and BB/M025489/1, and by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent projects BBS/E/F/000PR10348 and BBS/E/F/000PR10349. W.L.C. was supported by the Research Foundation—Flanders (FWO SB PhD fellowship 1S40018N); J.P.R. was financially supported by the Belgian Directorate General for Development Cooperation (DGD). M.A.B. and N.R.T. were supported by Wellcome funding to the Sanger Institute (#206194). The work done in Benin, Burkina Faso and DRC by B.B., L.M.-K., M.-F.P., D.F., D.A., J.J. and O.L. was funded by the Belgian Directorate of Development Cooperation (DGD) through the Multi-Year Programme (2012–2016) between the Belgian DGD and the Institute of Tropical Medicine, Belgium and (for DRC) by the Baillet-Latour find and the Flemish Interuniversity Council (VLIR-UOS). The isolates from Malawi were generated by Malawi Liverpool Wellcome Research Programme bacteraemia service, supported by Asia and Africa Programme Grant 206545/Z/17/Z to NF. The work in The Gambia was supported by the Bill & Melinda Gates Foundation (OPP1020327); GAVI The Vaccine Alliance’s Accelerated Development and Introduction Plan (PneumoADIP), Medical Research Council (UK) to GM. Salmonella isolates obtained through the RTS,S study was funded by the Bill & Melinda Gates Foundation to CAM. Salmonella isolates obtained through the TSAP study were funded by the Bill & Melinda Gates Foundation to IVI (OPPGH5231) to F.M., H.J.J. and S.E.P. This research by S.V.P., S.S. and G.D. was funded by the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This research was funded in whole, or in part, by the Wellcome Trust (#206194).Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Invasive non-typhoidal Salmonella (iNTS) disease manifesting as bloodstream infection with high mortality is responsible for a huge public health burden in sub-Saharan Africa. Salmonella enterica serovar Typhimurium (S. Typhimurium) is the main cause of iNTS disease in Africa. By analysing whole genome sequence data from 1303 S. Typhimurium isolates originating from 19 African countries and isolated between 1979 and 2017, here we show a thorough scaled appraisal of the population structure of iNTS disease caused by S. Typhimurium across many of Africa’s most impacted countries. At least six invasive S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2 driving the current pandemic. ST313-L2 likely emerged in the Democratic Republic of Congo around 1980 and further spread in the mid 1990s. We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance. Our work provides an overview of the evolution of invasive S. Typhimurium disease, and can be exploited to target control measures
