A genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic resistance in sub-Saharan Africa

Invasive 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

Salmonella Typhi whole genome sequencing in Rwanda shows a diverse historical population with recent introduction of haplotype H58.

Acknowledgements: We are grateful to Mr Belamo Niyigena and Mr Bertin Ushizimpumu from the National Reference Laboratory Division at Rwanda Biomedical Centre for their technical assistance.Funder: Belgian Directorate General for Development Cooperation (DGD)Funder: Gates (TyVAC Consortium)Funder: Research Foundation Flanders (FWO)Funder: Baillet-LatourSalmonella enterica serovar Typhi (S. Typhi) is the cause of typhoid fever, presenting high rates of morbidity and mortality in low- and middle-income countries. The H58 haplotype shows high levels of antimicrobial resistance (AMR) and is the dominant S. Typhi haplotype in endemic areas of Asia and East sub-Saharan Africa. The situation in Rwanda is currently unknown and therefore to reveal the genetic diversity and AMR of S. Typhi in Rwanda, 25 historical (1984-1985) and 26 recent (2010-2018) isolates from Rwanda were analysed using whole genome sequencing (WGS). WGS was locally implemented using Illumina MiniSeq and web-based analysis tools, thereafter complemented with bioinformatic approaches for more in-depth analyses. Whereas historical S. Typhi isolates were found to be fully susceptible to antimicrobials and show a diversity of genotypes, i.e 2.2.2, 2.5, 3.3.1 and 4.1; the recent isolates showed high AMR rates and were predominantly associated with genotype 4.3.1.2 (H58, 22/26; 84,6%), possibly resulting from a single introduction in Rwanda from South Asia before 2010. We identified practical challenges for the use of WGS in endemic regions, including a high cost for shipment of molecular reagents and lack of high-end computational infrastructure for the analyses, but also identified WGS to be feasible in the studied setting and giving opportunity for synergy with other programs

A genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic resistance in sub-Saharan Africa

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

A genomic appraisal of invasive Salmonella Typhimurium and associated antibiotic resistance in sub-Saharan Africa

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

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

Peer reviewed: TrueFunder: Canadian Institutes of Health Research; FundRef: http://dx.doi.org/10.13039/501100000024Funder: National Institute for Health Research; FundRef: http://dx.doi.org/10.13039/501100000272Funder: Institut Pasteur and Santé Publique FranceFunder: Bill and Melinda Gates Foundation; FundRef: http://dx.doi.org/10.13039/100000865Funder: Indian Council of Medical Research; FundRef: http://dx.doi.org/10.13039/501100001411Funder: World Health Organization and Gavi, the Vaccine AllianceFunder: Department for Health and Social Care, the Department for International Development/Global Challenges Research Fund, the UK Medical Research Council, and the Wellcome TrustFunder: Wellcome; FundRef: http://dx.doi.org/10.13039/100010269BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210])