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

描述（由申请人提供）：由于利什曼病造成的全球疾病负担很高，目前有多达1200万人感染，每年有1- 200万新病例发生，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，通过感染的白蛉白蛉叮咬传播。已知有超过20种利什曼原虫引起疾病，其范围从自限性皮肤病变到潜在致命的内脏疾病，主要取决于致病寄生虫种类。最致命的疾病形式是由杜氏乳杆菌引起的，杜氏乳杆菌主要在印度次大陆流行，其致病机制，特别是关于其表型变体的机制仍然知之甚少。斯里兰卡是受利什曼病影响的新焦点，迄今为止收集的证据指向存在遗传上不同的杜氏利什曼病菌株，其表现出向皮性的非典型表型特性，在此建议使用临床，生物学和最新的分子技术进行深入研究。深入了解杜氏乳杆菌种内的此类菌株变异将能够更好地了解该种的毒性特性，进而在未来开发更有效的诊断和有效的治疗方法。该提案的广泛目标是研究在斯里兰卡引起皮肤利什曼病（CL）的杜氏利什曼原虫的表型和基因型特征。具体而言，将通过对CL临床/病理学后遗症的研究，采用临床和血清学标准对患者进行长期随访，确定寄生虫的基本亲皮性。第二，在已建立的动物模型中研究寄生虫毒力的体内外相关性，即巨噬细胞侵袭和疾病后遗症。第三，建议使用美国合作者建立的利什曼原虫小环DNA足迹分析法对当地杜氏利什曼原虫菌株进行详细的遗传特征分析，该方法是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，该检测将能够深入分析在斯里兰卡引起CL的寄生虫分离株的遗传特征。总的来说，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，这将有助于减少全球疾病负担，为印度次大陆消除疾病的努力做出积极贡献。 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，尽管它导致高发病率和死亡率，特别是在发展中国家的贫困社区。更好地了解致病寄生虫的遗传结构及其变化，这项拟议研究的目标，将使开发高效和有效的工具，以协助控制战略，以打击这种毁灭性的疾病，并加强消除努力，在印度次大陆的整体效果，减少全球疾病负担。

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.