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

采用多学科方法研究东非内脏利什曼病 (VL) 和黑热病后皮肤利什曼病 (PKDL) 传播和发病机制的生态型

• 批准号: 10598163
• 负责人: Damaris Matoke
• 金额: $ 43.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598163
• 关键词: Address; Africa; Amphotericin; Animals; Asia; Automobile Driving; Behavior; Biology; Blood; Bone Marrow; Breeding; Case Study; Cause of Death; Cells; Cessation of life; Chromosomes; Chronic; Classification; Clinical; Collaborations; Collection; Copy Number Polymorphism; Country; Data; Dermal; Development; Disease; Disease Progression; Eastern Africa; Ecology; Epidemiology; Ethiopia; Frequencies; Genes; Genetic; Genotype; Goals; Gossypium; Growth; Human; Image; Immune; Infection; Integration Host Factors; Intrinsic factor; Isoptera; Kenya; Knowledge; Left; Leishmania donovani; Leishmania infantum; Leishmaniasis; Lesion; Life; Liposomes; Liver; Longevity; Malaria; Maps; Mutation; Nature; Organ; Outcome; Parasites; Parasitic Diseases; Paromomycin; Pathogenesis; Pathway interactions; Patients; Persons; Phagocytes; Phlebotominae; Phlebotomus; Post Kala-Azar Dermal Leishmaniasis; Prevention strategy; Proliferating; Public Health; Recommendation; Reporting; Research; Rest; Risk; Risk Factors; Sand Flies; Seasons; Serology; Site; Skin; Soil; Somalia; Source; South Sudan; Spleen; Sudan; Tropism; Uganda; Vector Ecology; Visceral Leishmaniasis; bacterial community; bone; density; disease phenotype; disease transmission; epidemiology study; feeding; global health; gut microbiota; healing; infection rate; innovation; interdisciplinary approach; lymphadenopathy; macula; neglected tropical diseases; novel therapeutics; parasite genome; potential biomarker; preference; skin lesion; transcriptome; transmission process; treatment comparison; treatment response; vector; vector competence; whole genome

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.

抽象的 目前有超过1200万人患有利什曼病，每年发生约200万例新病例，这使得 一个主要的全球健康问题，并将其归类为忽视的热带疾病。内脏利什曼病（VL）是 利什曼原虫Donovani和Leishmania Infantum引起的疾病威胁生命形式，IS 以寄生虫向肝脏，脾和骨髓传播为特征。第二，VL原因是疟疾 寄生疾病中的大多数死亡。据报道，大多数由多诺瓦尼乳杆菌引起的VL病例 东非，特别是肯尼亚，苏丹，南苏丹和埃塞俄比亚。在苏丹，有40-50％的治疗VL患者 开发Kala Azar Dermal Leishmaniasis（PKDL），其特征是寄生虫在 皮肤导致黄斑或结节性皮肤病变。 pkdl在大多数中自我固化，但多达20％的案件 成为慢性和非修复。 PKDL病变最近被认为是沙子感染的来源 苍蝇。东非的VL是一种流行病学和临床上多样化的疾病。在东非，两个截然不同 埃塞俄比亚北部和苏丹东部的VL的生态型，北部生态型（NE-VL）以及南部的生态型 （SE-VL）在埃塞俄比亚南部，肯尼亚，乌干达和索马里，已经根据遗传差异确定 在寄生虫以及不同的沙蝇载体物种和生态特征。 Phlebotomus Martini（南部 生态型）对白蚁丘（繁殖 /静止地点）具有微生物偏爱；和P. Orientalis （北部生态型）取决于黑色棉质土壤裂缝。疾病表型和临床结果也有所不同 在两种生态型和北部生态型之间。例如，PKDL在NE-VL中很常见，但在 se-vl。此外，尽管北部埃塞俄比亚和苏丹具有相似的寄生虫，但PKDL很常见 在苏丹，但在北部埃塞俄比亚很少见。同样，对多霉素的治疗反应也有所不同 与SE-VL相比，NE-VL对治疗的反应较差。与亚洲不同，在东方的VL 非洲是针对控制的目标，而不是通过谁来消除谁，部分是由于大量知识差距 生态ePidemiology，载体生物学以及宿主和寄生虫因素驱动传播和发病机理。 VL 传播受到内在因素的影响，例如矢量能力，寿命和肠道菌群，以及 外部因素包括储层多样性，矢量喂养偏好和拟人化的媒介源性， 其他的。然而，这些因素如何促进东非和其他地方的VL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个站点研究VL的生态流行病学 在东非的SE-VL（2个地点）或NE-VL（2个地点）的地方，并且具有不同的生态学 传输特征（AIM 1），确定影响向量行为和的因素的相对重要性 生态学作为传播的驱动因素（AIM 2），并确定VL中发病机理的宿主和寄生虫决定因素 和PKDL（AIM3）。总的来说，我们的研究将有助于VL知识格局，控制和 在东非，创新机会和针对VL和PKDL消除的新疗法。