Hsp90 as a modulator of pathogenicity, virulence and transmission in veterinary infections caused by Theileria and Babesia species

In terms of wide-scale human poverty, rural regions of South Asia are some of the most afflicted places on earth. In India alone, 400 million people may be considered to live in extreme poverty. Many of these people are dependent on dairy cattle for food and income. Increased production from livestock represents an important way to contribute to poverty reduction. However livestock productivity is impeded by the presence of pathogens such as Theileria annulata. In India alone, losses due to T. annulata infection are estimated to be in the region of $400 million per annum. It is more difficult to put a figure on potential losses due to Babesia infection in India as this parasite is less well studied, but infections are on the rise, possibly due to climate change and the increased spread of the tick vector. A recent sero-prevalence study indicated infection levels of 56% in cattle from endemic zones of Uttar Pradesh and Punjab. Both parasites are transmitted by ticks and infect cattle when the tick takes a blood meal. Infection can result in death, which is devastating for poor farmers with a small number of animals. Those animals that survive infection show significant reductions in productivity. Thus new control measures are desperately needed to break the cycle of infection.

For both tropical theileriosis and babesiosis, current control relies either on the use of a live vaccine, drug treatment, or the application of acaricides, all of which suffer from various limitations. Difficulties with quality control and the maintenance of a cold-chain, restricts delivery of the live vaccines to large numbers of animals across rural India. Reversion to virulence is possible and transmission of viral pathogens via the Babesia vaccine has occurred. The available live vaccines do not induce a sterile immunity, and vaccinated animals are likely to become infected, significantly reducing their productivity. While crossbred cattle are more resistant to infection, there is a pay-off because production relative to European cattle is reduced, and crossbred calves are still susceptible to disease. Drugs, such as buparvaquone, kill Theileria but are expensive; additionally drug resistance has been reported from different parts of the world and is a growing threat. Drugs for the treatment of Babesia infections are similarly limited: Imizol, the only licensed drug in the UK requires a long withdrawal period. In some parts of the world acarcidides are extensively used to control ticks, but the development of resistance and the environmental damage associated with these chemicals limits their long-term usefulness.

Studies in other apicomplexan parasites have demonstrated an essential role for Hsp90 in differentiation, infection and virulence. Hsp90 is a well-characterised molecule in many other systems and importantly many specific small molecule inhibitors are available. T. annulata infected cells adopt several characteristics of tumour cells (uncontrolled proliferation, ability to metastasize) and, as Hsp90 plays an important role in many cancer cells in maintaining the transformed phenotype, we believe that it may hold the key to understanding the pathogenicity of Theileria infection. In addition, the availability of small molecule inhibitors of Hsp90, designed for use in tumours, offers the potential for repurposing of these compounds to important infections of livestock.

The tick-borne apicomplexan parasites Theileria annulata and Babesia spp. are important pathogens of domestic animals and a major threat to global food security. Tropical theileriosis, caused by T. annulata, is a significant disease of bovines in India with losses estimated at $400 million per annum. Babesiosis caused by Babesia bovis, B. bigemina and B. divergens is a comparatively neglected disease in India. However it is endemic in India and a growing threat to the livestock industry due to the spread of the tick vector. We hypothesize that Hsp90 plays a critical role in these organisms, facilitating the transmission between vector and mammalian host, influencing virulence and pathogenicity and modulating the response to other stresses such as drug exposure. Hsp90 is an essential protein in all eukaryotic cells, acting as a molecular chaperone for a select group of client proteins such as transcription factors, kinases and other signalling molecules. When Hsp90 is inhibited, client proteins are targeted for degradation via the proteasomal pathway resulting in cell death. The central role that Hsp90 plays in many cell types has led to the development of many small molecule inhibitors, several of which are in advanced stage clinical trials for the treatment of specific cancers. Studies on tumour cells have identified an extracellular Hsp90 that is a determinant of cellular invasiveness via the chaperoning of matrix metalloproteinases (MMPs). Since infection with Theileria results in the uncontrolled proliferation and MMP-mediated metastasis of infected cells, determining whether parasite Hsp90 may play a similar role is important to understanding the pathogenesis of tropical theileriosis. As well as providing novel insight on the basic biology and host-parasite relationship, information from this project could be exploited to examine the potential of Hsp90 as a novel drug target in apicomplexan parasites, including those endemic in the UK.

The major impact of this work is likely to be felt in India and in other nations where tick-borne diseases severely limit livestock productivity and threaten food security for small and large scale farmers alike. Both T. annnulata and Babesia can decimate livestock and thus threaten food security at a global level. By providing a new paradigm to explain the pathogenicity and virulence of these parasitic infections, our project has the potential to devise novel methods of control based on the repurposing of existing drugs. Given the issues with the available methods of controlling both infections, the time is ripe for a novel approach to better understanding their biology at a molecular level with a view to translating these findings into treatment. If successful, our research outputs could be capitalised upon by a commercial pharmaceutical company aiming at improved control of Babesia infections, which are widespread in Europe and T. annulata, which is present in parts of southern Europe. Alternatively, the results of our project may be picked up by an NGO, for example, with a commitment to improving animal health in resource-poor settings. Food security includes animals which are a major source of protein for many susbsistence farmers in countries such as India and thus any small steps taken to improve the health of their livestock can translate into major gains for the farmer, his family and thus the economy of that country.

As the project is an international collaboration between scientists in the UK and India, we anticipate that the impact of this research will help strengthen the scientific and economic basis of cooperation between our countries. Tick-borne diseases are an increasing threat in Europe (including the UK) because of climate change and the increasing spread of the vectors. Not only do they threaten livestock farming, but they are also important in human medicine (e.g. Lyme Disease) and in wildlife. In addition, results from this project will also impact on other apicomplexan parasites that are endemic in the UK. Thus our programme of research could contribute to health and wealth of both countries (and additional ones) by limiting the impact of these diseases. By establishing these joint links, we also hope to build long-lasting relationships with our Indian partners, facilitate the exchange of technology in both directions and allow younger scientists the opportunity to experience the value of working in a different country.

Prof Shiels has excellent links with a worldwide network of researchers working on tick-borne disease through the EU Marie Curie network POSTICK and thus the potential to build upon this strategic partnership to enhance knowledge exchange and cooperation. Prof Devaney is a member of the management committee of SPASE (Strategic Partnership for Animal Science Excellence) funded by the Rural and Environment Science and Analytical Services (RESAS) Division of the Scottish Government which seeks to put bioscience research on animal health and welfare in Scotland firmly on the global map. Through SPASE we interact with a variety of external stakeholders including Pharma, representatives of the farming/agricultural industry, and Government, as well as researchers in other Institutes and Universities. Moreover, Knowledge Exchange and Impact is recognised as increasingly important at the University of Glasgow where a new KE and Impact strategy has recently been launched which aims to help researchers communicate their findings more widely and interact with a range of stakeholders so that the benefit of research and training carried out at Glasgow is maximised.