Molecular epidemiology of ticks and tick-borne disease, host resistance and development of novel pathogen vaccines

Tick-borne diseases (TBD) affect 80% of the world's cattle population, and are a significant threat to global food security. Tropical theileriosis caused by Theileria annulata is an important tick borne disease of cattle and buffalo in India, with estimated losses of $499 million per annum). Cattle and buffalo are also infected with Babesia, and the rickettsia, Anaplasma and Erlichia. Control of TBD has been largely by using acaracides to kill ticks but resistance and environmental damage are reducing the use of these compounds. Drug treatment is available but the cost is prohibitive for many farmers and with recent reports of parasite drug resistance, is not a long-term option for control. Live vaccines have been developed but have problems in terms of production, delivery, the treat of disease and transmission of contaminating infections. Vaccinated animals are likely to become infected and generate a carrier state that, for theileriosis, caiusese considerable economic loss. Thus, new methods of control are needed for the future if livestock productivity and food security is to be increased.

There is not a wealth of epidemiological data from India on TBD. Available studies primarily used classical parasitological methods and limited to small geographical areas and cross sectional sampling. Knowledge of the relative importance of the pathogens and tick species, and the role of cattle breeds and buffalo in transmission and clinical disease is sketchy. T. annulata, Babesia bigemina and Anaplasma marginale range in prevalence across different regions and the most common tick vectors are Hyalomma anatolicum anatolicum and Rhipicephalus microplus. In general it is known that, young calves suffer clinical disease and most adult animals carry the infection but disease is less common. Both buffalos and native cattle are more resistant to disease compared to highly productive European breeds, which are highly susceptible. However, there is a pay-off with breeds that are disease resistant, because production is reduced, and crossbred calves are still susceptible to disease. Moreover, it has been shown that animals carrying Theileria parasites suffer substantial economic loss. For full productivity a disease free state requires to be reached. To develop more effective control strategies it is necessary to understand in detail TBD epidemiology in India. Genetic traits that confer breed resistance also need to be identified so that resistant animals with higher productivity can be bred. Strategies that also operate to block pathogen transmission by ticks should also be studied, since the ideal scenario for full productivity is a disease free state.

The proposed project will have three related aims/objectives: 1) undertake an extensive molecular epidemiological analysis of tick borne disease and develop models to predict the impact of different approaches of control; 2) investigate the nature of breed resistance with respect to infection with Theileria annulata and 3) develop novel vaccines against tropical theileriosis, with emphasis on blocking transmission of the pathogen by the tick vector. All three objectives are designed to provide greater knowledge of the status of TBD in India with emphasis on improvement of strategies to control disease and reduce economic loss. While infections transmitted by ticks are a greater priority for India, significant levels of disease in livestock in the UK are caused by tick borne pathogens: e.g. Anaplasma (Tick borne fever), staphlycoccal bacteria (Tick pyaemia), Babesia (Red water fever) and the louping ill virus. Developing tools and models for epidemiology of TBD and investigating the nature of breed resistance and transmission blocking strategies is, therefore, of relevance to both countries.

Tick-borne diseases (TBD) affect 80% of the world's cattle population, and are a significant threat to global food security. Tropical theileriosis caused by Theileria annulata is an important tick borne disease of cattle and buffalo in India, with estimated losses of $499 million per annum). Cattle and buffalo are also infected with Babesia, and the rickettsia, Anaplasma and Erlichia. Current control of TBD in India is via a combination of acaracides, anti-parasite drugs, vaccination with parasites attenuated for virulence and cross breeding for natural resistance. All these strategies have limitations such as resistance of ticks to acarcides and pathogens to drugs, delivery and production problems for vaccines and a loss of productivity in breeds resistant to disease. Moreover, animals carrying T. annulata have been associated with > 50% of production loss. Thus, new methods of control are needed if food security is to be increased, the ultimate goal being a disease free situation and full potential productivity. The proposed project will have three related aims/objectives: 1) undertake an extensive molecular epidemiological analysis of tick borne disease and model the impact of different control strategies; 2) using a systems based biology approach, investigate the nature of within and between breed resistance to infection with T. annulata and 3) investigate the impact of antigenic diversity on antigens that are candidates for a transmission blocking vaccine against tropical theileriosis in order to develop a strategy that counters the ability of the parasite to evade an immune response. All three objectives are designed to develop and improve of strategies to control TBD and reduce economic loss, in India. Such strategies will also be value to the UK since significant levels of disease in livestock in the UK are caused by tick borne pathogens: Anaplasma, Staphlycocci, B. divergens and the louping ill virus.

Tick borne pathogens are a major causes of disease in livestock, generate costs of £ billions, and impact significantly on the livelihood of millions of people. In India many people live in rural areas that have a high prevalence of tick borne disease (TBD), in particular tropical theileriosis, and are dependent on dairy cattle for income and nutrition. High calf mortality can be devastating for poor farmers with a small number of beasts and the 14% loss of lactation estimated for tropical theileriosis is particularly serious. TBD also impact on production efficiency and profit of large-scale livestock systems. TBD is relevant to Europe and the UK, with the threat from TBD likely to increase with changes to climate and spread of tick vectors. This proposal aims to perform research for development of novel control strategies against TBD. As such it has potential to improve food security and enhance the quality of life of humans over much of the world.
Potential beneficiaries of the research are:
(1) The animal health industry is concerned with maintaining food-security by developing products, including vaccines, to control infectious disease. It also aims to develop cattle breeds with improved genetic backgrounds. The proposed research will focus on a major tick borne disease of cattle in India and develop knowledge that will lead to identification of genetic markers linked to disease resistance. It also aims to develop strategies for a vaccine with potential to block pathogen transmission and counter antigenic diversity. This research will be of benefit for development of next generation vaccines and livestock breeds.
(2) Academics and companies wishing to improve control against related apicomplexans of livestock. Although of most relevance to T. annulata, related parasites cause major diseases. These include T. lestoquardi in the Middle East and T. parva in Africa. Improving breed resistance and blocking transmission is also relevant to Babesia of cattle and horses. Countering antigenic diversity is of relevance to other TBD agents (e.g. Anaplasma) and parasites (e.g. Plasmodium)
(3) Livestock producers. Losses in livestock due to TBD are of major economic significance through death, loss of growth and milk yield. Strategies aimed at providing resistance to TBD and preventing losses caused by carrier animals would have substantial impact.
(4) Health and quality of life in the developing world. Many people in Asia and Africa live in extreme poverty and operate as small-holder farmers. Their animals are at great risk from babesiosis, theileriosis and anaplasmosis. Research that provided novel targets for improved next generation vaccines and development of more resistant productive breeds would have significant impact.
(5) International Policy makers: The Millennium Development Goals provides a universal framework for developing countries and partners towards eradicating hunger and poverty. For this to occur increased efficiency of livestock based agriculture is required. Productive, resistant livestock and vaccines that block infection would have impact on this policy.

Timescales for impact to be realised: short term (3 years), characterisation of antigen diversity of transmission blocking candidates and identification of biomarker profiles associated with resistance; medium term (5-10 years), circumvention of antigen diversity and testing of transmission blocking vaccine, identification of genetic loci associated with resistance: longer term (10-15 years), development of a recombinant vaccine that protects against disease and blocks transmission of tropical theileriosis, breeding of productive animals resistant to TBD. Skills, training and knowledge economy: staff employed on the project will develop key interdisciplinary skills that will be valuable for UK and Indian industry e.g. identifying markers of breed resistance, modeling infectious disease risk and vaccine development.