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

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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.