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Investigating the bacterial trapping properties of septins

LSHTM staff: Serge Mostowy
Funding: Wellcome Trust Senior Research Fellowship, ERC Consolidator Grant, Lister Institute of Preventative Medicine
Collaborators: Rut Carballido-López (FR), Martin Pilhofer (CH)

In 2010, researchers first observed that filament-forming proteins called septins, which form part of our immune system, can form cages that entrap Shigella bacteria. This finding opened up the prospect of harnessing these proteins to stop bacteria spreading in the body, potentially providing a completely new way of treating resistant infections.

Shigella is a human gut pathogen that infects more than 150 million people globally and causes up to 500,000 deaths every year. Due to the increasing number of drug resistant strains, Shigella is one of the 'superbugs’ deemed a priority by the World Health Organization.

The team is investigating exactly how septins interact with Shigella, including which parts of the septin proteins interact with certain targets on bacterial surfaces, the fate of entrapped bacteria, and how septins can differentiate between different types of pathogens.

Their findings have so far shown that septins are able to recognise Shigella cells that are dividing, and that once entrapped these cells are flagged to the immune system and destroyed.  

By comparing the behaviour of septins as they interact with different bacterial species, they have also revealed that septins change their behaviour depending on the shape of the bacterial cell and the specific targets found on the bacterial surface.

In their next steps, the team aims to identify the full breadth of septin targets on different types of bacteria, and gain a better understanding of how septins interact with them for their assembly into cages. It is hoped this understanding will lead to the clinical application of septins for bacterial diseases that are becoming harder to treat through resistance to existing antibiotics.

Selected outputs:

Febrile Illness Evaluation in a Broad Range of Endemicities (FIEBRE)

LSHTM staff: Prof David Mabey, Oliver Baerenbold, Dr John Bradley, Victoria Gould, Dr Heidi Hopkins, Eulalia Iglesias, Sham Lal, Michael Lawrence, Ruth Lorimer, Dr Chrissy Roberts, Dr Shunmay Yeung
Funding: UK Foreign, Commonwealth and Development Office
Collaborators: Liverpool School of Tropical Medicine, Barcelona Institute for Global Health (ISGlobal), University of Oxford, University of Otago

FIEBRE is a multi-disciplinary study investigating the causes of febrile illness at multiple sites in sub-Saharan Africa and Southeast Asia where there is currently little information and very limited diagnostic capacity for the management of patients with fever. The study aims to recruit a total of 9,600 patients overall, both children and adults, and more than 2,400 community controls in order to generate, for the first time, a detailed description of the infectious causes of fever in the study regions.

The main research objectives are to:

  • Identify the most common infectious causes of fever that are treatable and/or preventable
  • Provide data on antimicrobial susceptibility of bacterial infections
  • Learn how local perceptions of fever affect treatment practices, including the use of diagnostics and antimicrobial drugs
  • Inform clinical guidelines and algorithms on how to manage patients with fever

The data collected will contribute to updated recommendations for the clinical management and prevention of febrile illnesses, and help with the design of new evidence-based guidelines for fever case management, adapted to local contexts.

We currently know little about the antibiotics being used to treat febrile illnesses and how we could safely reduce antimicrobial use. FIEBRE will provide a platform for monitoring antimicrobial susceptibility in the study areas, as well as employing social science research to understand relationships with antibiotics in different communities, and how we can optimise their use in fever case management.

These data will help to ensure patients receive treatments that give them the best chance of recovery, as well as help stop the spread of antimicrobial resistance.

Metagenomic screening for AMR in malnourished children

LSHTM staff: Jackie Knee, Chloe Hutchins
Funding: ACF Fondation, USAID/BHA
Collaborators: Action Contre la Faim
Project duration: 2020-2023

The spread of antimicrobial resistance (AMR) is a threat to global public health, economy and security. The reduction in the effectiveness of antibiotics poses risks to children, especially those who suffer from severe acute malnutrition (SAM). These children have a high risk of mortality from infectious diseases such as diarrhoea and pneumonia. SAM affects an estimated 17 million children, most of whom are in sub-Saharan Africa and Asia.

The Community Management of Acute Malnutrition approach treats non-complicated SAM as outpatients, who remain at home and follow outpatient treatment programs that include broad-spectrum antibiotics such as amoxicillin. These programmes have a high failure rate and some studies have questioned the effectiveness of antibiotic treatment for SAM. The researchers of this study suggest that one reason for this might be the presence of resistant pathogens among these children.

Stool samples will be collected from children discharged from SAM outpatient treatment programmes  in Senegal and South Sudan and sent to LSHTM for the detection of enteropathogens. The authors will perform additional metagenomic analyses of the samples to screen for a wide range of AMR genes and determine the prevalence of clinically relevant resistance genes using qPCR. These results will help us to better understand the potential for AMR infections among these vulnerable populations.

The research team will work within national and global offices of the NGO Action Contre la Faim / Action Against Hunger (ACF/AAH) to facilitate uptake of research results, including spreading awareness of the potential scope of AMR infections among SAM populations and rethinking current recommendations for antibiotic treatment.

Genomic surveillance of Klebsiella for neonatal sepsis vaccine development

LSHTM staff: Kathryn Holt, Ebenezer Foster-Nyarko, Kara Tsang
Funding: Bill & Melinda Gates Foundation
Collaborators: Oxford Big Data Institute, Institut Pasteur
Project duration: 3 years

Klebsiella pneumoniae is a globally prioritised pathogen due to the severity of the disease as well as its broad antimicrobial resistance. It is a major cause of neonatal sepsis, ranking in the top three causative agents in most settings. However, there is a lack of systematic surveillance data and limited understanding of the genomic epidemiology of the pathogen.

This study aims to use technical solutions to develop a comprehensive platform for K. pneumoniae genomic surveillance, enabling researchers to gather and analyse whole genome sequences and epidemiological data from around the world.

The researchers have already developed the tools Kleborate, a genomic surveillance framework and genotyping tool for K. pneumoniae, and Pathogenwatch, a tool led by the Centre for Genomic Pathogen Surveillance, for rapid genomic characterisation and surveillance of Klebsiella. They will integrate these with BIGSdb, a database developed by the Institut Pasteur, that serves as the core repository for genomic data for K. pneumoniae.

In this project, these existing tools will be extended and integrated to provide a one-stop solution for genomic surveillance of Klebsiella, the KlebNET Genomic Surveillance Platform. KlebNET aims to make the power of genomic surveillance accessible to researchers, clinical microbiologists and epidemiologists to use without need for specialist knowledge of Klebsiella or genome analytics.

In doing so, the project will support valuable, real-time data about Klebsiella infections and outbreaks, including the specific genetic makeup of the bacterial strain.This will allow scientists to identify important genetic markers for virulence, drug resistance and surface antigens, which will be used to inform K. pneumoniae vaccine development for neonatal sepsis.

Outputs:

Modelling the cost-effectiveness of AMR interventions in Vietnamese chicken and pig farms

LSHTM staff: David Tresco Emes, Gwen Knight, Nichola Naylor, Jeff Waage, Jo Lines
Funding: CGIAR A4NH
Collaborators: ILRI, OUCRU
Project duration: 2019-2021

Antibiotics are widely used in livestock to prevent and treat infectious diseases, however this can lead to drug-resistant infections that can spread to people, posing a risk to human health.

It’s therefore important that the use of antibiotics in livestock is reduced. Farmers can compensate for this by improving animal husbandry and biosecurity interventions, or alternatively, the antibiotics used in livestock can be replaced with others that are less important to human medicine.

This study is using computer modelling to predict the long-term cost-effectiveness of implementing such interventions in Vietnamese chicken and pig farms.

The researchers are exploring the effect of different variables, including a variety of human infections, methods of estimating workforce productivity loss from disease, the link between animal antimicrobial use and human AMR, and the background growth rate of AMR, over different timeframes.

Their outputs will include estimates of the cost savings to farmers, costs saved to human healthcare and the costs of implementing the changes.

Preliminary results indicate that these interventions can be highly cost-effective, and it’s hoped these findings will encourage policymakers and farmers to reduce our reliance on antibiotics for food production.

Download infographic of the model

AMR historical foresight: comparing AMR to climate change and tobacco control

LSHTM staff: Virginia Berridge
Funding: AHRC
Collaborators: University of Exeter, RAND Europe, University of East Anglia, Tyndall Centre for Climate Change Research, University of Oslo
Project duration: Dec 2017 – Feb 2020

This study aims to understand how AMR has developed as a policy issue by adopting a historical and comparative perspective. By looking at the historical development of climate change and tobacco control as comparator issues, the researchers are examining whether there are lessons that can be learnt  for future AMR scenario planning and decision-making. All three issues share their complexity, enduring nature and significant public health consequences.

The project combines a historical and foresight analysis with engagement with policymakers and key stakeholders in order to achieve three objectives: to understand how AMR has evolved as a policy issue and develop scenarios for policymaking responses informed by historical analysis, to test these scenarios to inform potential policy responses, and to provide evidence for effective and efficient AMR policymaking and methodological development through the use of historical perspectives to inform policy.

Information for this project was collected from review of previous evidence, interviews, methods including horizon scanning and scenario planning and interactive policy events that gather historians and policymakers, the latter being an important part of the project.

MBIRA (Mortality from Bacterial Infections Resistant to Antibiotics)

LSHTM staff: Alex Aiken, Andrea Rehman
Funding: Bill & Melinda Gates Foundation, Fleming Fund
Collaborators: Centre for Infectious Disease Research in Zambia (Lusaka, Zambia), Haramaya University (Harar, Ethiopia), Kilimanjaro Clinical Research Institute (Moshi, Tanzania), KEMRI-Wellcome Trust Research Programme (Kilifi, Kenya), Malawi-Liverpool-Wellcome Trust Clinical Research Programme (Blantyre, Malawi), National Hospital Abuja (Abuja, Nigeria), Stellenbosch University (Stellenbosch, South Africa), University of Ghana Medical School (Accra, Ghana), Université des Sciences, des Techniques et des Technologies de Bamako (Bamako, Mali).
Project duration: October 2019 – March 2022

Whilst AMR is a global issue, it has major implications for African countries where severe bacterial infections are common but access to effective antibiotic treatment remains limited. To date, we lack reliable estimates of the impact of AMR in LMIC settings, which limits our capacity to address the increasing threat.

The MBIRA project is the first multi-national prospective observational study to better understand the mortality burden due to AMR in bloodstream infections in sub-Saharan Africa. The project is focussed on bacteraemia caused by Gram-negative enteric bacteria and includes patients of all age groups, from neonates to adults. The aim is to gather data across 9 hospitals in sub-Saharan Africa to inform larger global burden of disease analyses.

Antibiotic stewardship in agricultural communities in Africa and Asia: A unified One Health strategy to optimise antibiotic use in animals and humans

LSHTM staff: Sian Clarke, Meenakshi Gautham, Eleanor Hutchinson, Catherine Goodman, Mishal Khan, Johanna Hanefield, Harprakash Kaur
Funding: GCRF Cluster Scheme
Collaborators: University of Glasgow, UK (Tiziana Lembo), RVC, UK (Pablo Alarcon, Ana Mateus, Fiona Tomlin), West Bengal University for Animal and Fishery Sciences, India (Indranil Samanta), Makarere University, Uganda (Freddy Kitutu, Anthony Mbonye), Universidad Antonio Narino, Colombia (Nelson Arenas)
Project duration: June 2020 - May 2021

This is a cluster project that seeks to compare and contrast emerging knowledge from recent and ongoing research across selected countries in Africa, Asia and South America about antibiotic usage and its drivers in humans and animals in agricultural communities and identify key priorities, potential points of nexus and barriers and enablers in order to facilitate the design of novel interventions with a common overarching strategy and contextual adaptations.

A multi-stakeholder approach towards operationalising antibiotic stewardship in India’s pluralistic rural health system

LSHTM staff: Meenakshi Gautham,  Catherine Goodman, Richard Stabler
Funding: MRC (HSRI)
Collaborators: Royal Veterinary College (Pablo Alarcon and Ana Mateus), Institute of Development Studies (Gerald Bloom and Ayako Ebata), Public Health Foundation of India (Prof. Srinath Reddy, Sanghita Bhattacharyya, Sandeep Bhalla), West Bengal University for Animal and Fishery Sciences (Indranil Samanta)
Project duration: Feb 2018 - Jan 2022

The main aims of the study are to engage with multiple stakeholders and co-design and implement (on a small scale) an intervention to operationalise antibiotic stewardship for human and livestock health in rural community settings in India. The intervention design will draw on formative research conducted with rural households, informal and formal primary care providers, veterinarians and paravets, health and regulatory department stakeholders, and stakeholders in pharmaceutical value chains in rural West Bengal, supplemented by an online survey of primary care physicians, informal providers, vets and paravets on their SARS-CoV-2-related practices, including use of antibiotics.

WASH and biosecurity interventions for reducing burdens of infection, antibiotic use and antimicrobial resistance

Funding: CGIAR
Collaborators: International Livestock Research Institute 
Project duration: 2019-2021
LSHTM staff: Chris Pinto, Clare Chandler, Sarai Keestra

This mixed methods systematic review investigated how water, sanitation and hygiene (WASH) and biosecurity interventions could reduce infections, antimicrobial use and antimicrobial resistance (AMR) in people working in close contact with animals, such as farmers. The researchers considered different settings, with a focus on low- and middle-income countries. Previous research had suggested that social, cultural, political, economic and environmental factors play an important role in the development of AMR, however, it was not well-understood how these effects could be mitigated. This systematic review, in collaboration with the International Livestock Research Institute (ILRI), aimed to summarise the evidence base for such structural AMR interventions, with the aim of shaping future research, policies and funding in this area.

A total of 104 studies were included in the review, which identified a number of effective interventions to reduce the burden of infections, antimicrobial resistance and antibiotic use in animal agricultural settings. Interventions which undertook biomanagement and bio-containment measures appeared to have positive effects most often. These measures attempted to create and maintain a conducive environment for animal raising in terms of physical infrastructure and protocols. The few studies reporting sanitation measures - which were similar to bio-containment interventions - all reported positive effects. By contrast, efforts to impact water quantity, water quality, and hygiene had more mixed effects on the outcomes assessed. Bio-exclusion interventions had mostly negative effects.

However, risk of bias was high or moderate in many studies, and publication bias should also be considered. These findings demonstrate the need for more, high-quality studies evaluating structural interventions. There are opportunities to learn from biosecurity Interventions for WASH and the authors propose that the 'A' In WASH represents both 'Animals' and 'Air', in recognition of these infection pathways. 

View the final report