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.

摘要