Characterising Toxoplasma gondii virulence: role of host and pathogen

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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.