Understanding differences in clinical presentations of cutaneous leishmaniasis in an endemic disease focus

了解地方病焦点中皮肤利什曼病临床表现的差异

• 批准号: MR/R01020X/1
• 负责人: Pascale Kropf
• 金额: $ 54.31万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR01020X%2F1
• 关键词: Understanding; differences; clinical; presentations; cutaneous

Leishmaniasis is one of the most important neglected tropical diseases: a group of diseases united by the fact that they impact the poorest communities and attract little political interest and less funding for control or basic research than other diseases. Transmitted by sandflies, leishmaniasis is a parasitic disease that affects an estimated 12 million people in 98 countries, causing disfiguring infections of the skin and other tissues, and tens of thousands of deaths. A striking feature of leishmaniasis is that diverse forms of the disease are caused by a single group of parasites. Visceral leishmaniasis (VL) occurs where parasites migrate and multiply in organs such as the liver and spleen. VL is usually fatal if not treated, as patients become immunocompromised and highly susceptible to other diseases. Cutaneous leishmaniasis (CL) is restricted to the skin and superficial tissues and can present in three different forms: localised CL (LCL) causes damage, such as small ulcers, only at the site of the insect bite; while other infections can be more widespread (diffuse CL; DCL) or when parasites invade and destroy mucosal tissue of the nose, lips or palate, leading to severe disfigurement (mucosal CL; MCL). There is a great variety in the severity of CL, with some infections healing spontaneously (usually LCL), while others persist and form large wounds. Healed lesions invariably result in scarring, which in some societies leads to severe social stigma and so has a profound impact on the lives of patients. These different forms of disease (known as clinical presentations) are associated with different species but there is substantial variation within species and it is poorly understood why Leishmania parasites cause different forms of disease. We propose to study CL in Ethiopia, where the disease is an important health problem. We will work in an area of North West Ethiopia, where Leishmania aethiopica is causing an increasing incidence of localised CL, diffuse CL and mucosal CL. Since the diseases occur in the same region and in the same human and vector populations, this focus is a unique place to unravel the biological basis of the different clinical presentation of CL. We will generate whole-genome data for parasites from each of the different presentations, and also quantify genome-wide host gene expression and the immune response to Leishmania infection in both the lesions and blood of patients with each form of CL. In this way we will identify the genes and types of immunity involved in particular types of CL. We have developed a non-invasive, painless way to sample CL-affected skin that allows us to take samples in the hard-to-reach communities most affected by the disease. The data from the clinical database will be used to explore if any clinical and epidemiological factors associated with the different presentations of CL in our cohort, but will also be included in the statistical analysis of the parasite and host data to identify and unravel associations with the different presentations. This study will elucidate the pathogenesis of CL, which is essential for the development of new strategies to prevent and treat leishmaniasis - both vaccines and better diagnostic tests. The project will also enhance capacity for biomedical research in Ethiopia and establish a framework for future research in this setting.

利什曼病是最重要的被忽视的热带疾病之一：这是一组疾病，因为它们影响最贫穷的社区，与其他疾病相比，很少引起政治兴趣，用于控制或基础研究的资金也较少。利什曼病由白蛉传播，是一种寄生虫病，影响98个国家的估计1 200万人，造成皮肤和其他组织感染毁容，数万人死亡。利什曼病的一个显著特点是，不同形式的疾病是由一组寄生虫引起的。内脏利什曼病（VL）发生在寄生虫迁移和繁殖的器官，如肝脏和脾脏。如果不治疗，VL通常是致命的，因为患者变得免疫功能低下并且对其他疾病高度敏感。皮肤利什曼病（CL）仅限于皮肤和浅表组织，可以以三种不同的形式存在：局部CL（LCL）仅在昆虫叮咬部位造成损害，如小溃疡;而其他感染可能更广泛（弥漫性CL; DCL）或寄生虫侵入并破坏鼻，唇或腭的粘膜组织，导致严重毁容（粘膜CL; MCL）。CL的严重程度有很大的差异，一些感染会自发愈合（通常为LCL），而另一些则会持续存在并形成大的伤口。治愈的病变总是导致疤痕，这在一些社会中导致严重的社会耻辱，因此对患者的生活产生深远影响。这些不同形式的疾病（称为临床表现）与不同的物种有关，但物种内存在很大的差异，人们对利什曼原虫寄生虫引起不同形式疾病的原因知之甚少。 我们建议在埃塞俄比亚研究CL，这种疾病是一个重要的健康问题。我们将在埃塞俄比亚西北部的一个地区开展工作，在那里，利什曼原虫引起局部CL、弥漫性CL和粘膜CL的发病率增加。由于这些疾病发生在同一地区，在相同的人群和媒介人群中，这一重点是一个独特的地方，以解开CL的不同临床表现的生物学基础。我们将从每种不同的介绍中生成寄生虫的全基因组数据，并量化全基因组宿主基因表达和对每种CL患者的病变和血液中利什曼原虫感染的免疫反应。通过这种方式，我们将确定涉及特定类型CL的免疫基因和类型。我们已经开发出一种非侵入性、无痛的方法来对受CL影响的皮肤进行采样，使我们能够在受疾病影响最严重的偏远社区进行采样。来自临床数据库的数据将用于探索是否有任何临床和流行病学因素与我们队列中不同表现的CL相关，但也将纳入寄生虫和宿主数据的统计分析中，以确定和阐明与不同表现的相关性。 这项研究将阐明CL的发病机制，这对于开发预防和治疗利什曼病的新策略至关重要-包括疫苗和更好的诊断测试。该项目还将提高埃塞俄比亚的生物医学研究能力，并为今后在这一背景下的研究建立一个框架。

项目成果

Diversity and Within-Host Evolution of Leishmania donovani from Visceral Leishmaniasis Patients with and without HIV Coinfection in Northern Ethiopia.

• DOI: 10.1128/mbio.00971-21
• 发表时间: 2021-06-29
• 期刊: mBio
• 影响因子: 6.4
• 作者: Franssen SU;Takele Y;Adem E;Sanders MJ;Müller I;Kropf P;Cotton JA
• 通讯作者: Cotton JA

A Way Straight-Forward for Leishmania Genetics.

利什曼原虫遗传学的一种直接方法。

• DOI: 10.1016/j.pt.2020.07.005
• 发表时间: 2020
• 期刊: Trends in parasitology
• 影响因子: 9.6
• 作者: Cotton JA