Characterising Toxoplasma gondii virulence: role of host and pathogen

刚地弓形虫是猫身上的一种寄生虫，可以感染所有温血动物，包括人类，它可以在免疫功能低下的人群中引起严重疾病，如艾滋病或癌症患者，以及在子宫内感染的儿童。世界卫生组织和疾病控制中心承认弓形虫病是世界范围内最重要的食源性疾病之一，也是食源性疾病中导致死亡的主要原因。该疾病还影响畜牧部门，是绵羊流产的主要原因。寄生虫的不同品系之间存在相当大的差异，有些品系的致病性比其他品系更强，特别是在南美洲，令人担忧的是，在那里，健康、免疫能力强的个人中报告了严重疾病的病例。一些菌株的高致病性引起了人们对弓形虫毒力的研究兴趣，以进一步了解宿主-寄生虫关系并预测疾病结局。虽然弓形虫被认为是一种主要的食源性病原体，但关于零售肉类在这种寄生虫传播中所起作用的数据严重缺乏——欧洲食品安全局最近强调了这一点。巴西是世界上肉类消费量最高的国家之一，因此确定肉类在弓形虫传播中的作用至关重要，特别是因为该地区主要是致病性较高的菌株。该项目将通过对巴西零售肉类进行首次全面研究，调查<s:1>圣保罗不同零售肉类样本中弓形虫的发病率、生存能力和遗传多样性，解决知识差距问题。通过巴西和英国之间的合作，将有可能在宿主特异性系统中评估从肉制品中分离出的弓形虫的毒力，以帮助确定不同分离株对公共和兽医卫生的风险。虽然小鼠已被证明是研究弓形虫毒力的一个极其重要的模型，但尚不清楚这些结果如何推断到其他宿主，如人类和绵羊。鉴于缺乏证据表明与其他动物相比，小鼠的疾病严重程度之间存在相关性，因此迫切需要一种更相关的、宿主特异性的系统来识别参与确定毒力和预测疾病结局的宿主和病原体因素。本项目旨在通过在体外研究小鼠、羊和人类细胞急性感染弓形虫毒株和非毒株时宿主-病原体的相互作用来解决这一重大知识缺口。该项目还将评估3D“迷你肠道”作为体外宿主特异性模型的适用性，用于研究毒力，提供一个独特而令人兴奋的实验系统，模拟感染的主要部位，从而减少对实验动物的依赖。总的来说，这个项目将使我们进一步了解食源性感染和寄生虫毒力。开发一种宿主特异性体外系统来表征弓形虫的毒力，将为研究毒力机制提供一个平台，这不仅可以预测特定宿主的疾病结果，还将有助于疫苗设计、更特异性的治疗方案以及开发新的药物化合物。

Toxoplasma gondii is a parasite of cats that can infect all warm-blooded animals, including humans where it can cause severe disease in immune compromised people, such as AIDS or cancer patients, and in children who were infected in utero. The World Health Organisation and the Centre for Disease Control recognise toxoplasmosis as one of the most important foodborne diseases worldwide and a leading cause of death amongst foodborne illnesses. The disease also impacts the livestock sector where it is a major cause of abortion in sheep. There is considerable variation between different strains of the parasite with some being more pathogenic than others, particularly in South America where, worryingly, cases of severe disease have been reported in healthy, immune competent individuals. The high pathogenicity of some strains has sparked much research interest on T. gondii virulence to further our understanding of the host-parasite relationship as well as predict disease outcome.Although T. gondii is recognised as a major foodborne pathogen, there is a significant lack of data on the role of retail meat in the transmission of this parasite - something which was recently highlighted as a knowledge gap by the European Food Safety Authority. Meat consumption in Brazil is amongst the highest in the world so it is crucial to determine the role of meat in transmission of T. gondii particularly since more pathogenic strains dominate in this region. This project will address the knowledge gap by conducting the first ever comprehensive study of retail meat in Brazil, investigating incidence, viability and genetic diversity of T. gondii in different retail meat samples in São Paulo. Through collaboration between Brazil and the UK, it will be possible to assess the virulence of T. gondii isolated from meat products in a host-specific system to help determine the risk of different isolates to public and veterinary health.While the mouse has proven to be an extremely important model for research into T. gondii virulence, it remains unclear how these results extrapolate to other hosts, such as humans and sheep. Given the lack of evidence of a correlation between the severity of disease in mice compared to other animals, there is an urgent need for a more relevant, host-specific system for identifying host and pathogen factors involved in determining virulence and predicting disease outcome. This project aims to address this significant knowledge gap by investigating the host-pathogen interactions during acute infection of mouse, sheep and human cells with virulent and non-virulent strains of T. gondii in vitro. The project will also assess the applicability of 3D "mini guts" as in vitro host-specific models for investigating virulence, offering a unique and exciting experimental system which mimics the primary site of infection thereby reducing the reliance on experimental animals.Overall, this project will allow us to further our understanding of foodborne infections and parasite virulence. The development of a host-specific in vitro system to characterise virulence of T. gondii will offer a platform to investigate the mechanisms of virulence which will not only allow for the prediction of disease outcome in specific hosts, it will also aid vaccine design, a more specific treatment regime as well as the development of new drug compounds.