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

志贺氏菌是低收入到中等收入国家5岁以下儿童腹泻疾病的主要细菌原因，每年导致约10万人死亡。尽管疾病负担很大，但志贺氏菌病的治疗和预防选择有限，没有获得许可的疫苗，志贺氏菌的抗菌素耐药性不断增加。志贺氏菌的进化和流行病学的高分辨率肖像可以通过对志贺氏菌分离株集合的整个基因组进行测序和比较(称为全基因组序列分析，WGSA)来实现，然后使我们能够设计最有效的志贺氏菌病的治疗和管理方案。例如，WGSA最近显示，在英国流行的一种特定亚型志贺氏菌在获得新的抗菌素耐药性类型后成为流行病，因此更新了治疗建议。然而，尽管WGSA提供了更多的洞察力，但还没有人将WGSA应用于受影响最严重的人群(即低收入到中等收入国家的5岁以下儿童)的一组具有代表性的志贺氏菌基因组，这对于在这一重要人口群体中提供治疗和预防信息是必要的。在这个项目中，我们将使用WGSA对从亚洲和非洲七个国家和地区(来自全球肠道多中心研究)的5岁以下儿童系统收集的1349株志贺氏菌分离株，以创建志贺氏菌流行病学和进化的相关、当代概述，为志贺氏菌病的治疗和管理提供信息。通过绘制志贺氏菌彼此之间以及与其他地方志贺氏菌的进化关系图，我们将确定志贺氏菌的哪些亚型是导致大部分疾病的原因。这样的分型方法对于世界范围内不尊重国界的腹泻病原体的流行病学追踪至关重要(志贺氏菌是高收入国家“旅行者腹泻”的常见原因)。我们还将确定志贺氏菌中占主导地位的抗菌素耐药性，并评估全球和区域治疗建议是否需要更新。至关重要的是，我们将探索目前正在开发的志贺氏菌疫苗是否可能基于在七个国家发现的病原体的多样性，并通过更好地表征志贺氏菌中一种被称为血清型转换的现象，在这种现象中，细菌可以通过简单的基因重排改变它们对人类免疫系统的看法。最后，我们将比较患病儿童和少数分离出志贺氏菌的健康儿童的分离株，看看是否可以确定导致人类疾病发展的因素。总体而言，这将创建我们对受影响最严重人群中志贺氏菌病的最新概述，并将有助于指导未来治疗和管理这一重要疾病的研究和战略。

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.