Genomic Epidemiology and Transmission of Campylobacter in Africa (GETcampy-Africa)

Diarrhoeal disease remains a major cause of child morbidity, growth faltering and mortality in low and middle income countries (LMICs), with Campylobacter among the most common causes. The major infection sources in the UK include contaminated food, but transmission routes in LMICs are unknown. This means that transmission among the children at highest risk (85% infected before 1yr in LMICs) is the least studied. House crowding, cohabitation with animals and poor sanitation/food safety are all potential risk factors, but effective interventions depend upon quantitative estimates of infection sources. So why is Campylobacter largely overlooked in LMICs? While the answer to this question, in part, relates to the perceived sub-clinical sporadic nature of infection and difficulties in culturing microaerophilic bacteria, a more unsettling reason is that the countries where people are at the greatest risk have low economic and development status. This realisation led to my decision to devote future research, and the knowledge and resources I have developed, to combat Campylobacter where my skills are most needed, in LMICs.

The epidemiology of campylobacteriosis is poorly understood in LMICs. In pilot studies, we have identified genomic variation in strains that may indicate differences in source, survival, transmission and virulence (compared to the UK). In particular, we have identified globally and locally distributed strains, evidence of within household spread and strains associated with asymptomatic infection and infection with other enteropathogens. Genome sequencing technologies and bioinformatics analysis provide a means for explaining these cryptic disease networks by identifying differences between strains from multiple sources, and tracking their transmission. However, the effective implementation of genomic source attribution relies not only on advanced comparative genomics techniques, but also the deployment of an appropriate sample frame and access to microbiology laboratories. To achieve this I have developed a network of collaborators, through several visits to Africa, that can undertake the required multicentre sampling (consistent with previous national-scale studies) including both broad cross-sectional sampling and sentinel site surveillance allowing calculation of the overall Campylobacter burden as well as case-control comparison to quantify asymptomatic infection. Information will feed into source attribution and monetised decision support models, to allow informed assessment of risk and targeted intervention through public health contacts. If funded, I will re-locate to The Gambia for 3-6 months of each year, at my own expense.

Building on an established collaborative network in the UK and Africa (The Gambia, Ghana, Burkina Faso), we will develop a program of globalized Campylobacter NGS surveillance. Specifically, we will: (i) sample and genome sequence thousands of isolates from animals, food, environmental sources and people (symptomatic, asymptomatic, and matched cases and controls); (ii) develop open-access databases and novel analysis pipelines (association study and machine learning) to characterize Campylobacter population structure and identify source attribution markers; (iii) quantify the relative contribution of different human infection sources; (iv) use a cost-benefit risk models to identify the most effective interventions in the transmission network. This evidence-based approach will enable effective local public health and policy interventions and focus efforts to reducing the burden of diarrhoeal disease in Africa.

Next generation sequencing (NGS) and comparative genomics approaches have considerable potential for describing the microbes associated with contamination sources, and the pathways to infection. However, this potential has been largely unmet in LMIC's, because of the significant challenges in handling the large amounts of pathogen genome data and interpreting it in the context disease epidemiology. GETCampy Africa will bring together leading researchers in enteric disease and enhance regional and international capability in genomic epidemiology and microbial source tracking in a program of capacity building, knowledge transfer and research through:

1. A co-ordinated sampling and analysis research program of surveillance and genome sequencing to investigate trends in Campylobacter infection and transmission between the environment, animals and human populations.

2. A freely accessible BIGS database of isolate genomes, containing >30K Campylobacter, genomes (and other enteropathogens) for contextualisation and linked to relevant metadata.

3. A web-accessible analysis environment, on UK/Gambia MRC-CLIMB cloud infrastructure, with instances customised for genomic epidemiology and a suit of workflows, pipelines, scripts, programs, and virtual machine images for genome analysis and source tracking.

4. A stochastic infection risk impact simulator based upon the quantitative source attribution data to model the impact of potential interventions on infection probabilities, and determine the most cost effective interventions.

5. An ambitious training and student exchange program that will include bootcamps, hackathons, and workshops, suitable for interested parties from public health scientists to undergraduate students.

The GETCampy program will deliver improvements in understanding of Campylobacter epidemiology, and build capacity in NGS and bioinformatics for enteropathogen research in Africa.

Diarrhoeal disease is among the most significant challenges in modern healthcare in LMICs. Some of the major causes, such as Campylobacter, are greatly under-reported and the decline in antibiotic effectiveness against enteropathogens is a major concern. Without national surveillance to characterize the source and extent of infections such as campylobacteriosis, interventions to reduce childhood morbidity and mortality will remain ineffective. The World Health Organisation and the European Centre for Disease Control have prioritized surveillance of multi-drug resistant gastrointestinal bacteria and through this interdisciplinary partnership initiative, incorporating state-of-the-art whole genome sequencing and bioinformatics, we will identify source/sink populations for improved surveillance, antimicrobial stewardship, and targeted interventions with direct benefit to the following groups.

1. The MRC Unit, The Gambia. This program will directly benefit the principal African collaborator. The UK partner will share expertise, provide training in microbiology and comparative genomics. This will build infrastructure and sustainability in intellectual property to help establish a Gambian national network for understudied enteropathogens and develop a new generation of African scientists equipped sustainable surveillance beyond the lifetime of the grant.

2. Gambian population. There are many serious infrastructure and cultural issues affecting the burden of Campylobacter infection in the population. By understanding the risk factors for infections, interventions - both physical and educational, can be implemented to improve population health. For example, by comparing different rural/urban cohorts we will be able to assess the impact of living quality and sanitation on infection and we will also be able to compare different population food/water sources, age groups, comorbidities etc.

3. Gambian Hospitals. We will enroll at 3 large clinic centres in The Gambia with the desire of improving patient diagnosis and management. This data will have a major influence on future projections and impact of understudied enteropathogens and therefore African healthcare strategies at local, regional and national level, including; improved categorizing of infections, infection control improvements, optimizing antimicrobial therapy.

4. Public health workers. Access to molecular surveillance data that will enable evidence-led strategic interventions informing control options. In addition, through environment/livestock/food sampling, changes can be made to decrease transmission and improve safe sustainable food production. Local economies will benefit from improved food production and reduced public health risks, while also providing legacy resources (genomes, and analysis methods) contributing to the international scientific community. Ultimately, a better understanding of understudied enteropathogens will contribute to improvements in the children's health in LMICs.

5. African National Policy Makers. Detailed characterisation and molecular epidemiology will benefit the international scientific community and lead to better understanding and improved bio-security and control. As well as having a real-time live website, project partners have considerable political influences and we will make six monthly reports to local and national health agencies in The Gambia, Ghana and Burkino Faso. Most notably, we will focus on the impact of campylobacteriosis on local patient populations, highlight the need for better protocols to prevent infection e.g. Safe Food Preparation Campaign, and seek additional funding beyond the life-time of the grant.

6. MSF/WHO/Pasteur Institute. Médecins Sans Frontières and the WHO have considerable interest in LMICs and in particular on the impact and burden of enteropathogen infection. The UK PI and African partners will liaise with these organisations and communicate data/findings.