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Characterising the influence of parasite variation on visceral leishmaniasis.

表征寄生虫变异对内脏利什曼病的影响。

基本信息

批准号：
MR/T016019/1
负责人：
Daniel Jeffares
金额：
$ 95.22万
依托单位：
University of York
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT016019%2F1
关键词：
Characterising influence parasite variation visceral

项目摘要

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.

内脏利什曼病，也称为黑热病，是一种被忽视的传染病，影响世界上98个国家的最贫穷人口，每年造成2万人死亡。黑热病是由单细胞利什曼原虫引起的，这些利什曼原虫通过白蛉转移并迁移到脾脏或骨髓等内脏器官。这种疾病如果不治疗往往是致命的。更好的治疗方法对于消除贫困社区的黑热病至关重要。在白蛉携带寄生虫的地区，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副作用，需要住院治疗，并且不能可靠地杀死所有寄生虫。抗药性寄生虫也进化了几次。即使药物确实治愈了患者，黑热病寄生虫也会持续存在于皮肤损害中，称为黑热病后皮肤利什曼病（PKDL）。重要的是治愈PKDL，因为病变含有活的寄生虫，它们是白蛉新传播的来源，并可能引发新的疾病爆发。目前，我们不知道为什么会发生PKDL，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PKDL发生在各大洲之间和国家内部。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也有不同的形式。这可能是由于人与人之间的遗传差异，或者因为利什曼原虫的寄生虫不同，所以引起不同类型的疾病。寄生虫变异对疾病变异的作用尚未完全确定。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，已知一些抗利什曼原虫药物在印度有效，但在巴西无效。研究寄生虫的变异也可以帮助我们了解寄生虫如何逃避免疫系统，并作为皮肤病变持续数月或数年。本项目将研究寄生虫遗传变异对黑热病和PKDL的影响。众所周知，东非含有最具遗传多样性的杜氏利什曼原虫生态型，因此非洲是研究这一点的最佳地点。我们将与东非的一项黑热病研究合作，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（共160名）中收集详细的临床和免疫细胞数据。患者血液中的免疫细胞将在治疗前，治疗后，然后几个月后，当PKDL可能发生。我们将在160名患者被诊断并参加研究时从他们身上分离利什曼原虫。我们将对寄生虫的基因组进行测序，并对它们之间的所有遗传差异进行详细的分类。因为每个物种的基因中都携带着它们的进化历史，我们可以用这些基因组来描述当前和历史上寄生虫在东非的迁移，显示生态类型是如何分布的。然后，我们将使用遗传学方法来确定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演变提供一些早期预警。利什曼原虫改变宿主免疫系统以逃避检测。因为我们将获得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是否更有效地逃避免疫系统。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。这项研究将产生一个更好的了解寄生虫引起黑热病和PKDL。这项研究可以帮助我们设计新的药物或新的疫苗，这样我们就可以消除这种疾病。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The genome of the zoonotic malaria parasite Plasmodium simium reveals adaptations to host switching.

DOI：
10.1186/s12915-021-01139-5
发表时间：
2021-10-01
期刊：
BMC biology
影响因子：
5.4
作者：
Mourier T;de Alvarenga DAM;Kaushik A;de Pina-Costa A;Douvropoulou O;Guan Q;Guzmán-Vega FJ;Forrester S;de Abreu FVS;Júnior CB;de Souza Junior JC;Moreira SB;Hirano ZMB;Pissinatti A;Ferreira-da-Cruz MF;de Oliveira RL;Arold ST;Jeffares DC;Brasil P;de Brito CFA;Culleton R;Daniel-Ribeiro CT;Pain A
通讯作者：
Pain A

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

R-loops和年龄衰老的裂变酵母细胞的调节变化驱动基因组重排的非随机模式。

DOI：
10.1371/journal.pgen.1009784
发表时间：
2021-08
期刊：
PLoS genetics
影响因子：
4.5
作者：
Ellis DA;Reyes-Martín F;Rodríguez-López M;Cotobal C;Sun XM;Saintain Q;Jeffares DC;Marguerat S;Tallada VA;Bähler J
通讯作者：
Bähler J

Candidates for Balancing Selection in Leishmania donovani Complex Parasites.

DOI：
10.1093/gbe/evab265
发表时间：
2021-12-01
期刊：
Genome biology and evolution
影响因子：
3.3
作者：
Grace CA;Forrester S;Silva VC;Carvalho KSS;Kilford H;Chew YP;James S;Costa DL;Mottram JC;Costa CCHN;Jeffares DC
通讯作者：
Jeffares DC

Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis.