A multidisciplinary approach to study ecotypes driving transmission and pathogenesis of Visceral Leishmaniasis (VL) and Post kala-azar dermal leishmaniasis (PKDL) in Eastern Africa

摘要 目前有超过1200万人患有利什曼病，每年新增约200万例，使其 这是一个重大的全球卫生问题，也是世卫组织列为被忽视的热带病。内脏利什曼病是一种 由杜氏利什曼原虫和婴儿利什曼原虫引起的危及生命的疾病 以寄生虫扩散到肝、脾和骨髓为特征。仅次于疟疾，VL导致 在寄生虫病中死亡人数最多。由杜诺瓦尼乳杆菌引起的大多数VL病例是从 东非，特别是肯尼亚、苏丹、南苏丹和埃塞俄比亚。在苏丹，40%-50%的VL患者接受治疗 发生黑热病后皮肤利什曼病(PKDL)，其特征是寄生虫在 皮肤导致黄斑或结节状皮肤损害。PKDL在大多数情况下可以自我解决，但高达20%的情况下 变得慢性且无法治愈。PKDL病变最近被认为是沙地的一个感染源。 苍蝇。在东非，VL是一种流行病学和临床多样化的疾病。在东非，两个截然不同的 VL的生态型，埃塞俄比亚北部和苏丹东部的北部生态型(NE-VL)和南部生态型 埃塞俄比亚南部、肯尼亚、乌干达和索马里的(Se-VL)已根据遗传差异被鉴定 在寄生虫中，不同种类的沙蝇媒介种类和生态特征不同。马提尼白头翁(南区 生态型)对白蚁土丘(繁殖/栖息地)有微生态偏好；和东方拟青蚁 (北方生态型)取决于黑棉土壤的裂隙。疾病表型和临床结果也各不相同。 在两个生态型之间和北方生态型内。例如，PKDL在NE-VL中很常见，但在 SE-VL。此外，尽管埃塞俄比亚北部和苏丹有基因上相似的寄生虫，但PKDL很常见。 在苏丹，但在埃塞俄比亚北部很少见。同样，对副霉素的治疗反应也存在差异。 与SE-VL相比，两性霉素脂质体NE-VL的疗效较差。与亚洲不同，VL在东方 非洲是世卫组织控制而不是消灭的目标，部分原因是在以下方面存在重大知识差距 生态流行病学、媒介生物学以及驱动传播和致病的宿主和寄生虫因素。vl 传播受到内在因素的影响，如媒介能力、寿命和肠道微生物区系，以及 外在因素包括水库多样性、媒介摄食偏好和媒介亲人性，其中 其他。然而，人们对这些因素如何促进VL在东非和其他地方的传播知之甚少。 为了解决这些知识差距，在这个U01项目中，我们建议在4个地点研究VL的生态流行病学 在东非，为东南-VL(2个地点)或NE-VL(2个地点)特有，具有不同的生态和 传播特征(目标1)，确定影响媒介行为的因素的相对重要性和 生态学作为传播的驱动力(目标2)，并确定VL发病的宿主和寄生虫决定因素 和PKDL(Aim3)。总体而言，我们的研究将有助于VL知识版图、控制和 东非消除VL和PKDL的创新机会和新疗法的发现。

Abstract Over 12 million people currently suffer from leishmaniasis, and ~2 million new cases occur each year, making it a major global health problem and a WHO classified neglected tropical disease. Visceral leishmaniasis (VL) is a life-threatening form of the disease caused by Leishmania donovani and Leishmania infantum and is characterized by parasite dissemination to the liver, spleen and bone marrow. Second to malaria, VL causes most deaths amongst parasitic diseases. The majority of VL cases caused by L. donovani are reported from East Africa, particularly Kenya, Sudan, South Sudan and Ethiopia. In Sudan, 40-50% of treated VL patients develop post kala azar dermal leishmaniasis (PKDL) which is characterized by proliferation of parasites in the skin leading to macular or nodular dermal lesions. PKDL self-resolves in the majority, but up to 20% of cases become chronic and non-healing. PKDL lesions have recently been implicated as a source of infection in sand flies. VL in eastern Africa is an epidemiologically and clinically diverse disease. in In East Africa, two distinct ecotypes of VL, the northern ecotype (NE-VL) in Northern Ethiopia and eastern Sudan and the southern ecotype (SE-VL) in southern Ethiopia, Kenya, Uganda and Somalia, have been identified based on genetic differences in parasites, and different sand fly vector species and ecological features. Phlebotomus martini (southern ecotype) have a micro-ecological preference for termite mounds (breeding /resting site); and P. orientalis (northern ecotype) depends on black cotton soil cracks. The disease phenotype and clinical outcomes also vary between the two ecotypes and within the northern ecotype. For example, PKDL is common in NE-VL but rare in SE-VL. Furthermore, although north Ethiopia and Sudan have genotypically similar parasites, PKDL is common in Sudan but rare in north Ethiopia. Likewise, there are differences in the therapeutic response to paramomycin and liposomal amphotericin as NE-VL responds poorly to treatment compared to SE-VL. Unlike Asia, VL in East Africa is targeted for control rather than elimination by WHO, partly due to significant knowledge gaps in ecoepidemiology, vector biology, and host and parasite factors driving transmission and pathogenesis. VL transmission is influenced by intrinsic factors such as vector competence, longevity and gut microbiota, and extrinsic factors including reservoir diversity, vector feeding preferences, and vector anthropophilicity, among others. Yet, how these factors promote VL transmission in Eastern Africa and elsewhere is poorly understood. To address these knowledge gaps, in this U01 project we propose to study the eco-epidemiology of VL at 4 sites in East Africa which are endemic for SE-VL (2 sites) or NE-VL (2 sites) and have different ecological and transmission features (Aim 1), determine the relative significance of factors that influence vector behavior and ecology as drivers of transmission (Aim 2), and identify host and parasite determinants of pathogenesis in VL and PKDL (Aim3). Collectively, our studies will contribute to VL knowledge landscape, control and innovation opportunities and discovery of new treatments towards VL and PKDL elimination in East Africa.