Study of cutaneous leishmaniasis in Sri Lanka caused by L.donovani

斯里兰卡多诺瓦尼利什曼病引起的皮肤利什曼病研究

• 批准号: 8288926
• 负责人: Nadira Dharshani Karunaweera
• 金额: $ 12.26万
• 依托单位: UNIVERSITY OF COLOMBO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288926
• 关键词: Affect; Africa; Animal Model; Asia; Biological; Biological Assay; Bite; Characteristics; Clinical; Communities; Cutaneous; Cutaneous Leishmaniasis; DNA Footprint; Data; Development; Diagnostic; Disease; Future; Genetic; Genetic Structures; Human; In Vitro; India; Lead; Leishmania; Leishmania donovani; Leishmaniasis; Lesion; Measures; Mesocricetus auratus; Methods; Modeling; Molecular; Morbidity - disease rate; Nature; Nepal; Parasites; Pathogenicity; Patients; Property; Sand Flies; Serological; South America; Sri Lanka; Techniques; Testing; Tropical Disease; Variant; Virulence; Virulent; Visceral; burden of illness; combat; effective therapy; follow-up; in vivo; macrophage; mortality; neglect; tool

DESCRIPTION (provided by applicant): The global disease burden due to leishmaniasis is high with as many as 12 million people currently infected, and 1-2 million new cases occurring each year, particularly in Africa, Asia and South America. It is considered as one of the least studied and most neglected of tropical diseases. The causative agent belongs to the genus Leishmania and it is transmitted via the bite of an infected phlebotomine sand fly. Over 20 species of Leishmania are known to cause diseases, which ranges from self-limiting cutaneous lesions to potentially fatal visceral disease, mainly depending on the causative parasite species. The most virulent form of disease is caused by L.donovani that is mostly prevalent in the Indian subcontinent and its pathogenetic mechanisms, particularly with regard to its phenotypic variants remain poorly understood. Sri Lanka is a new focus affected by leishmaniasis with the evidence gathered so far pointing towards the presence of genetically distinct strains of L.donovani that demonstrates an atypical phenotypic property of dermotropism, which is proposed here to be studied in depth using clinical, biological and latest molecular techniques. In depth understanding of such strain variations within the L.donovani species would enable better understanding of the virulent properties of this species and in turn would lead to the development of more efficient diagnostics and effective treatment methods in the future. The broad objective of this proposal is to study the phenotypic and genotypic characteristics of L.donovani that cause cutaneous leishmaniasis (CL) in Sri Lanka. Specifically, the essential dermotropic nature of the parasites will be determined through studies on the clinical/pathological sequelae of CL by long-term follow up of patients using clinical and serological criteria. Secondly, to study in vivo and in vitro correlates of parasite virulence, viz macrophage invasion and disease sequalae in established animal models. Thirdly, detailed genetic characterizations of local L.donovani strains is proposed to be done using Leishmania mini-circle DNA footprint assay, which has been established by the US collaborators, as an efficient and effective method to differentiate inter and intra-species sequence variations. Hence, this assay would enable in depth genetic characterization of parasite isolates that cause CL in Sri Lanka when analyzed together with similar data from strains that cause visceral disease in India and Nepal. Overall, this study is meant to enable better understanding of the pathogenicity of L.donovani, which in the long term would help reduce the global disease burden contributing positively towards the disease elimination efforts in the Indian subcontinent. PUBLIC HEALTH RELEVANCE: Leishmaniasis is one of the least studied and most neglected of tropical diseases in spite of the high morbidity and mortality it causes, especially in poor communities in the developing world. Better understanding of the genetic structure and its changes in the causative parasite, the objective of this proposed study, would enable the development of efficient and effective tools to assist control strategies to combat this devastating disease and enhance the elimination efforts that are in place in the Indian subcontinent with overall effect of reducing the global disease burden.

描述（由申请人提供）：利什曼病造成的全球疾病负担很高，目前感染者多达 1200 万人，每年出现 1-200 万新病例，特别是在非洲、亚洲和南美洲。它被认为是研究最少和最被忽视的热带疾病之一。病原体属于利什曼原虫属，通过受感染的白蛉叮咬传播。已知超过 20 种利什曼原虫可引起疾病，范围从自限性皮肤损伤到潜在致命的内脏疾病，主要取决于致病寄生虫种类。毒性最强的疾病是由多诺瓦尼李斯特菌引起的，该细菌主要流行于印度次大陆，其发病机制，特别是其表型变异仍知之甚少。斯里兰卡是受利什曼病影响的一个新焦点，迄今为止收集的证据表明存在遗传上不同的杜诺瓦尼利什曼菌株，该菌株表现出亲肤性的非典型表型特性，这里建议使用临床、生物学和最新的分子技术对其进行深入研究。深入了解杜氏乳杆菌物种内的此类菌株变异将有助于更好地了解该物种的毒力特性，进而促进未来更有效的诊断和有效治疗方法的开发。该提案的主要目标是研究在斯里兰卡引起皮肤利什曼病 (CL) 的多诺瓦尼利什曼病 (CL) 的表型和基因型特征。具体而言，寄生虫的基本亲皮肤性质将通过使用临床和血清学标准对患者进行长期随访，对 CL 的临床/病理后遗症进行研究来确定。其次，在已建立的动物模型中研究寄生虫毒力、即巨噬细胞入侵和疾病后遗症的体内和体外相关性。第三，建议使用美国合作者建立的利什曼原虫小环DNA足迹测定法来完成当地利什曼原虫菌株的详细遗传特征，作为区分种间和种内序列变异的有效方法。因此，当与印度和尼泊尔引起内脏疾病的菌株的类似数据一起分析时，该测定将能够对在斯里兰卡引起 CL 的寄生虫分离株进行深入的遗传表征。总体而言，这项研究旨在更好地了解杜氏乳杆菌的致病性，从长远来看，这将有助于减轻全球疾病负担，为印度次大陆的疾病消除工作做出积极贡献。 公共卫生相关性：利什曼病是研究最少和最被忽视的热带疾病之一，尽管其发病率和死亡率很高，特别是在发展中国家的贫困社区。这项拟议研究的目的是更好地了解致病寄生虫的遗传结构及其变化，这将有助于开发高效和有效的工具，以协助控制策略来对抗这种毁灭性的疾病，并加强印度次大陆的消除努力，从而总体上减轻全球疾病负担。