An integrated approach to tackling drug resistance in livestock trypanosomes.

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Drug resistance is an increasing problem for many diseases worldwide. Trypanosomes are tsetse-fly transmitted single-celled organisms that cause serious disease in cattle - African Animal Trypanosomiasis (AAT), mainly in sub-Saharan Africa, where approximately 60 million cattle are at risk and AAT kills 3 million each year. The main measure farmers have to combat AAT is drug treatment, but we only have two main drugs, both of which are >50 years old and widely used. Resistance to these drugs is increasingly reported, and there are very few drugs in the development pipeline, meaning the current control methods have very doubtful sustainability. Despite being such a significant issue, we know very little about how trypanosomes resist the effect of the drug, and how AAT drug resistance emerges and spreads. Therefore we are limited in our ability to deploy informed strategies to mitigate the problem. This project aims to generate data and resources to bridge these knowledge gaps. The applicants have been working in an area in Northern Tanzania since 2011. Recently farmers have been reporting drug treatment failure and the need to use increasing amounts of the prophylactic drug Isometamidium chloride (ISM) more frequently, suggesting emerging resistance.We already have samples from 5,000 cattle and 10,000 tsetse flies, as well as information on farmer drug use, from a cohort of farms in the area sampled between 2011 and 2017. Additionally, we have developed resources and capabilities for working on the relevant trypanosome species, Trypanosoma congolense, in the laboratory (most information derives from the human-infective Trypanosoma brucei, but it is increasingly apparent that these are very distinct organisms). This platform of preliminary data and resources will be used to answer our central hypothesis, that the management of animal trypanosomiasis in Tanzania is threatened by an emerging failure of ISM to provide adequate prophylaxis. To test this hypothesis, we will address four main research questions: (i) what are the likely mechanisms by which resistance to ISM occurs and can we identify a marker?; (ii) what are the extent and cause of ISM failure?; (iii) what are the epidemiological consequences of ISM failure?; and (iv) how might resistance to trypanocides, including new drugs, be prevented? To achieve this we will: (1) identify ISM resistance mechanisms by generating resistant parasites in the laboratory and comparing resistant and susceptible parasites using biochemical, molecular and genomic analysis; (2) collect field data in the same area in order to assess drug use and drug quality, isolate drug resistant parasites, and assess the epidemiology of drug use and drug resistance in the field; (3) using data combined from the laboratory and the field, generate a mathematical model whose parameters are informed by both the laboratory and field data, allowing us to accurately assess how resistance emerges and spreads in AAT in the field; and (4) apply the model and predict scenarios that will inform on the selection and spread of resistance for a new trypanocidal compound in development by our industrial partners, GALVmed. The outputs of this project would provide unprecedented and detailed insight into the epidemiology of AAT drug resistance, uncover mechanisms of drug resistance in the disease-relevant trypanosome species (including potential markers), and will develop the first application of mathematical modelling, importantly using accurate parameters, to provide insights into the dynamics of AAT drug resistance emergence and spread. As well as providing novel insights, the outputs have the potential to inform drug development and drug usage, by identifying strategies that will have the best chances of mitigating resistance, and therefore maximising the lifetime of both existing and novel drugs.