Characterising the influence of parasite variation on visceral leishmaniasis.

内脏利什曼病，也被称为黑热病，是一种被忽视的传染病，在98多个国家中影响着世界上最贫穷的人，每年导致2万人死亡。黑热病是由单细胞利什曼原虫引起的，这种寄生虫通过沙蝇转移并迁移到内脏，如脾或骨髓。如果不治疗，这种疾病往往是致命的。更好的治疗对于从贫困社区消除黑热病至关重要。在沙蝇携带寄生虫的地区，没有疫苗可以保护人们。用于治疗这种疾病的药物可能会导致痛苦的不良反应，需要住院治疗，而且不能可靠地杀死所有寄生虫。耐药寄生虫也进化了好几次。即使药物确实治愈了患者，黑热病寄生虫也会持续存在称为黑热病后真皮利什曼病(PKDL)的毁容皮肤病变。治愈PKDL很重要，因为病变中含有活体寄生虫，它们是沙蝇新传播的来源，并可能助长新的疾病爆发。目前，我们不知道PKDL发生的原因，也不知道如何阻止它。大多数黑热病病例发生在巴西、埃塞俄比亚、印度、肯尼亚、索马里、南苏丹和苏丹。不同形式的黑热病和黑热病发生在大陆之间和国家内部。例如，PKDL在东非的一些地区很常见，但在其他地区从未发生过。非洲和印度的PKDL也采取了不同的形式。这可能是由于人与人之间的遗传差异，也可能是因为利什曼原虫不同，所以引起的疾病种类不同。寄生虫变异对疾病变异的作用尚不清楚。了解寄生虫之间的差异很重要，因为它们可能需要不同的治疗方法，例如，众所周知，一些抗利什曼原虫的药物在印度有效，但在巴西无效。研究寄生虫的变异也可能有助于我们理解寄生虫是如何逃避免疫系统，并作为皮肤病变持续数月或数年的。本项目将研究寄生虫的遗传变异对黑热病和PKDL的影响。众所周知，东非拥有遗传多样性最大的杜氏利什曼原虫生态型，因此非洲是研究这一生态型的最佳地点。我们将与东非的一项kala azar研究合作，该研究正在从苏丹、埃塞俄比亚、肯尼亚和乌干达各40名患者(总共160人)收集详细的临床和免疫细胞数据。患者将在治疗前、治疗后和几个月后发生PKDL时采集血液中的免疫细胞。当160名患者被诊断并登记参加研究时，我们将从他们中分离出利什曼原虫。我们将对寄生虫基因组进行测序，并制作出它们之间所有遗传差异的详细目录。由于每个物种的基因都带有它们的进化史，我们可以使用这些基因组来描述当前和历史上寄生虫在东非的迁徙，显示生态型是如何分布的。然后，我们将使用遗传方法来确定不同寄生虫之间的差异是否会导致黑热病症状的差异或导致PKDL。我们将能够对苏丹、埃塞俄比亚、肯尼亚或乌干达的抗药性寄生虫的进化提供一些早期预警。利什曼原虫改变宿主免疫系统以逃避检测。因为我们将拥有每个患者的详细免疫细胞数据，我们还可以确定某些寄生虫在逃避免疫系统方面是否更有效。最后，我们将能够确定特定的寄生虫基因是否帮助它们逃避免疫系统，导致PKDL或允许它们抵抗药物。这项研究将对引起黑热病和PKDL的寄生虫有更好的了解。这项研究可能会帮助我们设计新的药物或新的疫苗，以便我们能够消除这种疾病。

Visceral leishmaniasis, also called kala azar, is a neglected infectious disease that affects the world poorest in over 98 countries, resulting in 20,000 fatalities a year. Kala azar is caused by single-celled Leishmania parasites that are transferred by sand flies and migrate to internal organs such as the spleen or bone marrow. The disease is frequently fatal if untreated. Better treatments are essential to eliminate kala azar from poor communities. There is no vaccine to protect people in regions where sand flies carry the parasite. Drugs that are used to treat the disease can cause painful adverse effects, require hospitalisation and do not reliably kill all the parasites. Drug-resistant parasites have also evolved several times. Even when drugs do cure patients, kala azar parasites can persist in disfiguring skin lesions called post-kala azar dermal leishmaniasis (PKDL). It is important to cure PKDL, because the lesions contain live parasites, they are sources of new transmission by sand flies and may fuel new disease outbreaks. At present, we do not know why PKDL occurs, or how to stop it.Most cases of kala azar occur in Brazil, Ethiopia, India, Kenya, Somalia, South Sudan and Sudan. Different forms of kala azar and PKDL occur between continents and within countries. For example, PKDL is common in some regions of East Africa, but never occurs in other regions. African and Indian PKDL also takes different forms. This may be due to genetic differences between the people, or because the Leishmania parasites are different, so cause different types of disease. The role of parasite variation on disease variation is not well established. It is important to understand the differences between parasites because they may require different treatments, for example it is known that some anti-Leishmania drugs are effective in India, but not effective in Brazil. Investigating parasite variation may also help us to understand how parasites evade immune systems and persist for months or years as skin lesions. This project will study the influence of parasite genetic variation on kala azar and PKDL. It is known that East Africa contains the most genetically diverse Leishmania donovani ecotypes, so Africa is the best place to study this. We will work with a kala azar study in East Africa that is collecting detailed clinical and immune cell data from 40 patients in each of Sudan, Ethiopia, Kenya and Uganda (160 in all). Patient immune cells in blood will be taken before treatment, after treatment, and then months later when PKDL can occur. We will isolate the Leishmania parasites from each of the 160 patients when they are diagnosed and enrolled in the study. We will sequence the parasite genomes, and produce a detailed catalogue of all the genetic differences between them.Because every species carries their evolutionary history in their genes, we can use these genomes to describe current and historic parasite migration across East Africa, showing how ecotypes are distributed. We will then use genetic methods to determine whether difference between parasites cause differences in kala azar symptoms or cause PKDL. We will be able to provide some early warning of the evolution of drug resistant parasites in Sudan, Ethiopia, Kenya or Uganda. Leishmania parasites alter host immune systems to evade detection. Because we will have detailed immune cell data from each patient, we can also determine whether some parasites are more effective at evading the immune system. Finally, we will be able to determine if specific parasite genes help them evade the immune system, cause PKDL or allow them to resist drugs. This study will produce a better understanding of the parasites that cause kala azar and PKDL. This research may help us to design new drugs or new vaccines so we can eliminate the disease.