Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids

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We propose to bring together a group of researchers across the UK and in Sao Paulo to share expertise that will allow us to understand the biology of parasites that cause neglected tropical diseases and improve our ability to intervene against them. Disease-causing microbes remain a major problem for health the world over. This is seen disproportionately in tropical countries, were a combination of environmental factors (e.g. climatic conditions supporting the propagation of insects that can transmit disease) and relatively scarce economic resource ensure the maintenance of infectious disease. Parts of rural Brazil, like other areas in Latin America, suffer from diseases caused by parasitic protozoa, which are single-celled organisms. One parasite, Trypanosoma cruzi, causes Chagas disease, affecting several million people across Latin America. Closely-related parasites, belonging to the genus Leishmania, cause a range of diseases called the leishmaniases in many parts of the world. Chagas disease is transmitted by triatomine bugs that suck the blood of mammals including humans and in the process defecate upon their victims. Parasites in the faeces then enter the body and over a long period of time, sometimes twenty years or more, the insidious Chagas disease develops. Quite often patients do not know they have the disease. In around 30% of cases though, a chronic inflammatory response to the heart or digestive system can lead to death. The leishmaniases are transmitted by sandflies through the saliva whilst they feed on their victims. Depending on which species of the Leishmania parasite is transmitted, the disease can either occur in the skin (cutaneous leishmaniasis) or else migrate to the liver and spleen (visceral leishmaniasis). Some species, including Leishmania braziliensis, causes the horrible disease known in Brazil as Espundia, where human cells called macrophages (in which the parasite resides) migrate to the mucosal membranes of our lips and nostrils and cause them to disintegrate. Sometimes, following treatment, after a lapse that can last a few years, the visceral form of the disease relapses into a form we call post Kalar-Azar dermal leishmaniasis (PKDL).Although drugs exist to treat both Chagas disease and the leishmaniases, they are far from ideal. Some are toxic, others have to be given over a protracted period, and several are available only by needle injections. Resistance has emerged to existing drugs, and it has been known for a long time that some parasites do not respond to treatment even if resistance has not been selected. This collaborative project aims to bring together a team of researchers across the UK and Sao Paulo to look specifically at the processes that enable parasites to thrive in the insect vectors that carry them and then within the very different environment of their mammalian host. Since the parasites keep exactly the same genome (which is the blueprint that encodes every aspect of their ultimate makeup) they need to choose which parts of the genome to express in different environments. This involves subtle changes to the structure of the protein architecture that holds their genes together, in a structure we call chromatin. In other organisms it has, in recent years, become clear that the addition of small molecules to those chromatin-associated proteins can change their function. Removing those adaptations causes them to change back again. These alterations, which do not involve modifying the sequence of the DNA blueprint itself, and yet do influence how that DNA is expressed, are described as "epigenetic" alterations. We will investigate how epigenetic alterations impact on gene expression in T. cruzi and leishmanias, and work out how we can manipulate this epigenetic process by altering the availability of the small molecule metabolites responsible for those changes. We hope to find new therapeutic drugs treatment interventions to act on these epigenetic targets.