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1200多万人患有利什曼病，每年有200万新病例， 这是一个重大的全球健康问题，也是世界卫生组织归类为被忽视的热带疾病。内脏利什曼病（VL）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形式， 以寄生虫散布到肝、脾和骨髓为特征。仅次于疟疾，VL导致 寄生虫病死亡人数最多。大多数VL病例由L.据报道， 东非，特别是肯尼亚、苏丹、南苏丹和埃塞俄比亚。在苏丹，40-50%接受治疗的VL患者 发生黑热病后皮肤利什曼病（PKDL），其特征是皮肤中寄生虫的增殖， 导致斑点状或结节状皮肤病变的皮肤。PKDL在大多数情况下自行解决，但高达20%的案件 变成慢性的和不愈合的。PKDL病变最近被认为是沙子中的感染源 苍蝇VL在东非是一种流行病学和临床上多样化的疾病。在东非， VL生态型、埃塞俄比亚北方和苏丹东部的北方生态型（NE-VL）和南方生态型 （SE-VL）在埃塞俄比亚南部、肯尼亚、乌干达和索马里，已经确定了基于遗传差异 不同白蛉媒介的种类和生态特征。马丁尼白蛉（南方 生态类型）对白蚁土丘（繁殖/休息场所）有微生态偏好;和P. orientalis （北方生态型）以黑棉土裂缝为主。疾病表型和临床结果也各不相同 在两个生态型之间和在北方生态型内。例如，PKDL在NE-VL中常见，但在NE-VL中罕见。 SE-VL。此外，尽管埃塞俄比亚北部和苏丹有类似的寄生虫基因型，PKDL是常见的 但在埃塞俄比亚北部很少见。同样，对巴龙霉素的治疗反应也存在差异 与SE-VL相比，NE-VL的脂质体庆大霉素对治疗的反应较差。与亚洲不同， 世卫组织将非洲作为控制而不是消除的目标，部分原因是非洲在以下方面存在巨大的知识差距： 生态流行病学、病媒生物学以及驱动传播和致病的宿主和寄生虫因素。VL 传播受内在因素的影响，如病媒能力、寿命和肠道微生物群， 外在因素，包括水库多样性，病媒取食偏好和病媒嗜食性， 他人然而，这些因素如何促进VL在东非和其他地方的传播知之甚少。 为了解决这些知识空白，在这个U 01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，它们是SE-VL（2个地点）或NE-VL（2个地点）的地方病，具有不同的生态和 传播特征（目标1），确定影响病媒行为的因素的相对重要性， 生态学作为传播的驱动因素（目的2），并确定VL发病机制的宿主和寄生虫决定因素 和PKDL（Aim 3）。总的来说，我们的研究将有助于VL知识景观，控制和 创新机会和发现新的治疗方法，以消除东非的VL和PKDL。

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.