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

利什曼病是最重要的被忽视的热带疾病之一：与其他疾病相比，利什曼病影响到最贫穷的社区，几乎没有引起政治兴趣，用于控制或基础研究的资金也较少，这是一组疾病。利什曼病通过沙蝇传播，是一种寄生虫病，在98个国家中估计有1200万人受到影响，导致皮肤和其他组织受到毁容感染，并导致数万人死亡。利什曼病的一个显著特征是，各种形式的疾病是由一组寄生虫引起的。内脏利什曼病(VL)发生在寄生虫在肝脏和脾等器官迁移和繁殖的地方。如果不进行治疗，VL通常是致命的，因为患者会变得免疫受损，并高度容易感染其他疾病。皮肤利什曼病(CL)仅限于皮肤和浅表组织，可以三种不同的形式出现：局限型CL(LCL)仅在昆虫叮咬部位引起损害，如小溃疡；而其他感染可更广泛(弥漫性CL；DCL)，或寄生虫入侵并破坏鼻、唇或腭部的粘膜组织，导致严重毁容(粘膜CL；MCL)。CL的严重程度有很大的不同，一些感染会自动愈合(通常是LCL)，而另一些感染会持续并形成大伤口。愈合的病变总是会导致疤痕，在一些社会中，这会导致严重的社会耻辱，因此对患者的生活产生深远的影响。这些不同形式的疾病(称为临床表现)与不同的物种有关，但物种间存在很大差异，人们对利什曼原虫导致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，在那里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工作，那里的利什曼原虫正在导致局限性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，在相同的人类和媒介人群中，这一焦点是揭示CL不同临床表现的生物学基础的独特之处。我们将从每一种不同的陈述中生成寄生虫的全基因组数据，并量化每种形式CL患者的皮损和血液中的全基因组宿主基因表达和对利什曼原虫感染的免疫反应。通过这种方式，我们将确定特定类型CL所涉及的基因和免疫类型。我们已经开发出一种非侵入性、无痛的方法来采样受CL影响的皮肤，使我们能够在受疾病影响最严重的难以到达的社区采集样本。来自临床数据库的数据将被用来探索是否有任何临床和流行病学因素与我们队列中不同的CL表现有关，但也将被包括在寄生虫和宿主数据的统计分析中，以识别和揭示与不同表现的联系。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，并为未来在这一背景下的研究建立一个框架。

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.