Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids

我们建议在英国和圣保罗召集一组研究人员，分享专业知识，使我们能够了解导致被忽视的热带病的寄生虫的生物学，并提高我们干预它们的能力。致病微生物仍然是全世界健康的一个主要问题。这种情况在热带国家尤为明显，在这些国家，环境因素（例如，气候条件有利于传播疾病的昆虫的繁殖）和相对稀缺的经济资源相结合，确保了传染病的维持。与拉丁美洲其他地区一样，巴西部分农村地区患有由寄生原生动物（一种单细胞生物）引起的疾病。一种寄生虫，克氏锥虫，会导致恰加斯病，影响拉丁美洲数百万人。密切相关的寄生虫属于利什曼原虫属，在世界许多地方引起一系列被称为利什曼病的疾病。恰加斯病是由锥蝽虫传播的，它们吸食包括人类在内的哺乳动物的血液，并在此过程中向受害者排便。然后，粪便中的寄生虫进入人体，经过很长一段时间，有时是20年或更长时间，潜伏的恰加斯病就会发展起来。病人往往不知道自己得了这种病。然而，在大约30%的病例中，心脏或消化系统的慢性炎症反应可能导致死亡。利什曼病是由白蛉以受害者为食时通过唾液传播的。根据传播利什曼原虫的种类，该病可发生在皮肤（皮肤利什曼病）或转移到肝脏和脾脏（内脏利什曼病）。一些物种，包括巴西利什曼原虫，会导致一种可怕的疾病，在巴西被称为Espundia，在这种疾病中，被称为巨噬细胞的人类细胞（寄生虫居住在其中）会迁移到我们的嘴唇和鼻孔的粘膜上，并导致它们分解。有时，在治疗后，经过可能持续几年的停顿，这种疾病的内脏形式复发为我们称之为后黑热病皮肤利什曼病（PKDL）的形式。虽然现有的药物可以同时治疗恰加斯病和利什曼病，但它们还远远不够理想。有些是有毒的，有些必须长期服用，还有一些只能通过针头注射获得。对现有药物的耐药性已经出现，而且人们早就知道，即使没有选择耐药性，一些寄生虫对治疗也没有反应。该合作项目旨在汇集英国和圣保罗的一组研究人员，专门研究使寄生虫在携带它们的昆虫载体中茁壮成长的过程，然后在它们的哺乳动物宿主的非常不同的环境中茁壮成长。由于寄生虫保持完全相同的基因组（这是编码其最终构成的每个方面的蓝图），它们需要选择基因组的哪些部分在不同的环境中表达。这涉及到将基因连接在一起的蛋白质结构的细微变化，这种结构我们称之为染色质。近年来，在其他生物体中，向染色质相关蛋白添加小分子可以改变它们的功能，这一点已经变得很清楚。移除这些适应性会使它们再次变回来。这些改变，不涉及修改DNA蓝图本身的序列，但确实影响DNA的表达方式，被描述为“表观遗传”改变。我们将研究表观遗传改变如何影响T. cruzi和利什曼原虫的基因表达，并研究如何通过改变导致这些变化的小分子代谢物的可用性来操纵这种表观遗传过程。我们希望找到新的治疗药物治疗干预措施来作用于这些表观遗传靶点。

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.