News Release 

Salmonella causing bloodstream infections in central Africa resistant to nearly all drugs

A multifaceted approach will be needed to track and control the spread of extensively drug-resistant Salmonella, including further microbiological and genomic surveillance

Wellcome Trust Sanger Institute

The first extensively drug-resistant (XDR) strains of Salmonella typhimurium, a pathogen which is responsible for millions of bloodstream infections per year in sub-Saharan Africa, have been identified in the Democratic Republic of Congo (DRC). Drug-resistance has increased in successive groups of S. typhimurium over time. These new strains are resistant to all but one of the commonly available drugs in the DRC, with one sample showing reduced susceptibility to this final antibiotic.

The study, published today (19 September 2019) in Nature Communications, was conducted by researchers from the Institute of Tropical Medicine (ITM) in Antwerp, the Institut National de Recherche Biomédicale (INRB) in the DRC, the Wellcome Sanger Institute, the University of Cambridge and their collaborators. The findings suggest that S. typhimurium has evolved in sub-Saharan Africa in the past decades and continues to do so. A multifaceted approach will be needed to track and control the spread of XDR Salmonella, including further microbiological and genomic surveillance.

Most Salmonella infections result in symptoms associated with food poisoning. While unpleasant, symptoms are not life-threatening in the vast majority of cases. But in sub-Saharan Africa, Salmonella such as S. typhimurium can cause infections of the blood, known as invasive non-typhoidal Salmonella (iNTS) infections.

Every year, iNTS infections are estimated to affect 3.4 million people and result in 681,316 deaths globally*, of which the majority are caused by S. typhimurium. The containment and treatment of iNTS infections in places like the DRC is complicated by limited access to healthcare, infrastructure challenges and weakened immunity, with children under five years of age particularly at risk.

It is known that iNTS infections in sub-Saharan Africa are dominated by a type of S. typhimurium known as ST313, which is associated with antibiotic resistance. Two groups of ST313 (named lineage I and II) split off independently and subsequently spread over the African continent. Antibiotic resistance has been growing over time, with lineage II now the primary cause of iNTS infections.

Now a global research partnership is working to understand how Salmonella ST313 continues to evolve and develop drug resistance. Working on blood samples collected in DRC hospitals from people with suspected bloodstream infections, researchers from the INRB and ITM observed antibiotic resistance levels never seen before in S. typhimurium causing bloodstream infections, including resistance to the antibiotic azithromycin - a drug normally held in reserve in case others prove ineffective**.

To better understand these findings these strains were genome sequenced and analysed, including bioinformatics analyses and laboratory experiments at ITM and the Wellcome Sanger Institute, and machine learning analyses at the Centre for Genomic Pathogen Surveillance (CGPS). Analysis of these S. typhimurium genomes identified a new sub-group that is branching off from ST313, named lineage II.1. Estimated to have emerged in 2004, this new group exhibits extensive drug resistance (XDR).

Dr Sandra Van Puyvelde, first author of the study from the Institute of Tropical Medicine and Visiting Scientist at the Wellcome Sanger Institute, said: "All antibiotic resistance genes contributing to 'XDR' are present on the same plasmid. This is worrying because a plasmid is a mobile genetic element that could be transferred to other bacteria. While accumulating more antibiotic resistance, we discovered that the novel Salmonella typhimurium line is also showing further genetic and behavioural changes which suggest ongoing evolution of the bacteria towards bloodstream infections."

The researchers also studied the way S. typhimurium is adapting to an invasive 'lifestyle', moving away from the forms of Salmonella that cause gastrointestinal illness towards the types that cause dangerous invasive bloodstream infections in sub-Saharan Africa. In addition to lab experiments, the samples were tested with a machine learning algorithm designed to look for characteristic patterns in the DNA of Salmonella that indicate the potential to cause dangerous invasive infections.

Dr Nicole Wheeler, a bioinformatician at the Centre for Genomic Pathogen Surveillance, based at the Wellcome Sanger Institute, said: "In the lab we've observed changes in this new group of Salmonella typhimurium that we've seen in other invasive salmonella. What's interesting as a bioinformatician is that we've been able to pick up these changes using machine learning. The hope is that in the near future we'll be able to deploy machine learning in a more predictive role to help control the emergence and spread of drug-resistant strains of bacteria such as S. typhimurium."

INRB and ITM have established bloodstream infection surveillance in the past ten years which has been pivotal in the early detection of the XDR S. typhimurium.

Professor Octavie Lunguya of INRB in the DRC, said: "We isolated the Salmonella typhimurium from patients in hospitals across the Democratic Republic of Congo during our bloodstream infection surveillance activities. It is now crucial that we closely monitor the bacteria and their progression."

Professor Gordon Dougan, from the University of Cambridge, said: "Studies like this are unique as we are making the bridge between the most important health issues observed in hospitals across the world with in-depth biological research for which we apply cutting edge technologies. Collaborations like this are key and will be important in the future to gain further insights on emerging diseases."

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Notes to Editors:

* For statistics and further information see 'Global Burden of Invasive Nontyphoidal Salmonella Disease' available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451910/

** For more information on how different drugs are used, see the WHO report 'Selection and Use of Essential Medicines 2017' available here https://www.who.int/medicines/publications/essentialmedicines/EML_2017_ExecutiveSummary.pdf?ua=1

Publication:

Sandra Van Puyvelde et al. (2019). A novel African Salmonella typhimurium ST313 sublineage with extensive drug-resistance and signatures associated with host adaptation. Nature Communications. DOI: 10.1038/s41467-019-11844-z

Funding:

This research was funded by the Belgian Directorate of Development Cooperation (DGD); the Flemish Interuniversity Council (VLIR-UOS); the Flemish Ministry of Sciences (EWI; SOFI project IDIS and fellowship S.V.P); the Baillet Latour Fund (The Bacterial Infections in the Tropics (BIT) research cluster at ITM Antwerp, Belgium) and Wellcome.

Selected websites:

The Institute of Tropical Medicine

The Institute of Tropical Medicine Antwerp (ITM), Belgium, works to advance medical science to improve the lives of people affected by tropical diseases and poor public health through fundamental and applied research, advanced education and expert services. Students from around the world specialise at ITM and our researchers seek a better understanding of tropical diseases, as well as the organisation and management of health care and disease control, in regions where needs are huge but means are limited. Every year, we vaccinate tens of thousands of travellers and offer preventive and clinical care to returned travellers. As a reference centre for tropical diseases, public health and HIV/AIDS, we provide expert advice and collaborate with partner organisations worldwide. http://www.itg.be

Institut National de Recherche Biomédicale (INRB)

INRB is a medical research institute located in Kinshasa, Democratic Republic of Congo (DRC). Its mission is to conduct basic, applied and operational biomedical research in support of national programs to fight diseases that have an impact on public health in DRC.

In the early 2000s, operational research, disease investigation and surveillance programs were initiated in collaboration with partners such as the World Health Organization (WHO) in order to strengthen national programs to combat epidemics and endemics in DRC (Poliomyelitis, HIV / AIDS, Cholera, Malaria, Trypanosomiasis, Invasive Salmonellosis ...).

Later on, applied research programs restarted in collaboration with partners such as the Institute of Tropical Medicine in Antwerp in Belgium, the National Institute of Health and the Centre for Control Diseases and Prevention in the USA. Today, INRB is one of few institutions in DRC that has the technical, infrastructural and scientific capacity to carry out high level research and training activities. In doing so, INRB and its partner teams help provide scientific evidence to guide health policies in DRC. The vision is to expand therapeutic and vaccine trials in order to bring the benefits of new treatments and vaccines to the population.

About the University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 107 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of the 'Cambridge cluster', which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents. http://www.cam.ac.uk [cam.ac.uk]

Centre for Genomic Pathogen Surveillance (CGPS)

To tackle anti-microbial resistance (AMR), we provide universal surveillance strategies at scale, facilitating rapid analysis and enabling the training of experts worldwide. The CGPS is committed to making our expertise in genomic pathogen surveillance as accessible as our data and tools. Find out more at https://www.pathogensurveillance.net/

The Wellcome Sanger Institute

The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast - we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at http://www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

About Wellcome

Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation.

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