Informing shigellosis treatment and management in resource-poor settings through pathogen genomics

Shigella are the leading bacterial cause of diarrhoeal disease in children under 5 years old in low- to middle-income nations and kill approximately 100,000 people per year. Despite this large disease burden, treatment and prevention options for shigellosis are limited, with no licenced vaccine available and increasing antimicrobial resistance in Shigella. High-resolution portraits of the evolution and epidemiology of Shigella can be achieved by sequencing and comparing entire genomes of collections of Shigella isolates (a process called Whole Genome Sequence Analysis, WGSA), which then allow us to design the most effective treatment and management options for shigellosis. For example, WGSA recently showed a specific subtype of Shigella circulating in the United Kingdom became epidemic after it acquired a new antimicrobial resistance type, so treatment recommendations were updated. Despite the increased insight afforded through WGSA however, no one has yet applied WGSA to a representative set of Shigella genomes from those populations most affected (i.e. children under 5 in low- to middle- income nations), which is necessary for informing treatment and prevention in this important demographic. In this project, we will use WGSA on 1349 systematically-collected Shigella isolates from children under 5 in seven countries across Asia and Africa (from the Global Enteric Multicentre Study) to create a relevant, contemporary overview of the epidemiology and evolution of Shigella to inform treatment and management of shigellosis.

By mapping the evolutionary relationships of the Shigella with each other, and with those from elsewhere, we will determine which subtypes of Shigella are responsible for causing most of the disease. Subtyping approaches such as these are crucial for worldwide epidemiological tracing of diarrhoeal pathogens, that do not respect international borders (Shigella is a common cause of 'traveller's diarrhoea' in high-income nations). We will also determine what antimicrobial resistances predominate in Shigella bacteria and evaluate whether global and regional treatment recommendations need to be updated. Crucially, we will explore whether current vaccines in development for Shigella are likely to work based on the diversity found in the pathogen across the seven countries, and by better characterising a phenomenon known as serotype switching in Shigella, where bacteria can change the way they look to the human immune system through simple genetic rearrangements. Finally, we will compare isolates from sick children and the few healthy children from whom Shigella was isolated to see if we can determine factors that contribute to development of disease in people. Collectively, this will create our most up-to-date overview of shigellosis in those populations most affected and will help direct future research and strategies for treatment and management of this important disease.

Shigellosis is the leading bacterial cause of moderate-to-severe diarrhoea in children under five years old in low-to-middle income nations. Our understanding of the agents of shigellosis, bacteria of the genus Shigella, is currently being transformed through Whole Genome Sequence Analysis (WGSA) studies which informs shigellosis treatment and management through an enhanced understanding of pathogen epidemiology, evolution and biology. However, WGSA studies on Shigella to date focused on defining population structures or characterising emerging national or risk-group-associated sublineages. To inform on treatment and management of shigellosis in its most important demographic, WGSA must be applied to a relevant, representative, contemporary collection of shigellae from endemic areas.
The Global Enteric Multicentre Study systematically-collected 1349 Shigella isolates from children under five years old from across Asia and Africa and represents just the collection needed to develop of most advanced overview of shigellosis to date relevant for informing treatment and management of the disease.

This project will achieve the following objectives:

1. Identify those Shigella subtypes and antimicrobial resistance profiles responsible for causing the most disease in the key demographic for shigellosis. This is crucial for epidemiological tracing and evaluating treatment recommendations.

2. Inform on the likelihood and potential timeframe of vaccine escape for both serotype-based and protein-based vaccine candidates currently in development for Shigella. We will work with industry to ensure our predictions are integrated into future development and implementation strategies.

3. Test the hypothesis that genomic factors are involved in the manifestation of clinical shigellosis by comparing Shigella isolates from case and control patients. This may identify novel pathogenesis factors for future functional research and perhaps therapeutic targeting.

This project will generate the most advanced and relevant overview of shigellosis and its antimicrobial resistance to date. As such, it will benefit stakeholders in various sectors, and will be delivered through continual engagement with these key groups over the course of the project, as well as a targeted stakeholders workshop to be held toward the completion of the project.

1. Public health beneficiaries will benefit from both the findings of the project and its utility as a public resource.

a. The antimicrobial resistance findings will be used to update treatment recommendations at national and potentially international levels. This will be of great direct benefit to public health at the sampling locations, all of which are DAC listed ODA recipients.
b. The data and findings will be made publically available and are essential for epidemiological tracing worldwide. In resource-poor settings where the data is less likely to be used directly, the development of low-cost diagnostics for surveillance will be explored.

2. Vaccine developers (both industrial and academic) will benefit from the findings of the project which will predict the likely efficacy of vaccine candidates currently in the public domain and generate data relevant to guiding future vaccine program implementation. Engagement with vaccine developers may lead to further collaboration on private-domain and/or novel vaccine candidates.

3. Public beneficiaries who will benefit through:

a. Improvements to health care provisions as a knock-on effect from the impact on public health (see 1) and
b. Enhanced understanding through public engagement with the project and the role of science in promoting health.

4. Academic beneficiaries through:

a. Scientific outputs that are significant across numerous fields, as well as an exemplar approach for value-adding through interdisciplinary collaboration
b. Skills development and an enhanced collaborative network in multiple early career researchers.