Characterization of Leishmania-Specific T cells in human skin and blood during cutaneous and mucocutaneous leishmaniasis

属于利什曼原虫属的寄生虫是人类病原体中最多样化的一种，无论是在地理分布上还是在由它们引起的各种临床症状上都是如此。目前，全球88个热带/亚热带国家有1200万人感染，每年报告的新增感染人数为200万人，3.5亿人面临感染风险。在过去的十年中，疫区的病例数量急剧增加。此外，由于与艾滋病毒合并感染，利什曼病正在向世界上几个非流行地区蔓延。目前可用的控制措施是发现病例和用药物治疗，这些药物价格昂贵，并不总是可用的，而且不能自行管理。抗药性寄生虫的激增进一步加剧了这一问题，迫切需要开发抗利什曼原虫疫苗或其他免疫疗法。研究已经证明了免疫在控制皮肤和粘膜自发性利什曼病方面的重要性，然而，这项工作的大部分是从患者的血液样本中进行的，而不是从皮肤感染部位进行的。在此背景下，目前的项目旨在描述在血液和皮肤中控制利什曼病的免疫机制。在这项建议中，我们的目标是首次将这一已建立的方法应用于人类局限性皮肤(LCL)和粘膜皮肤利什曼病(MCL)的研究，以了解与皮肤和血液中细胞发育、功能和调节相关的免疫机制。通过这项工作，我们将能够确定感染过程中涉及的皮肤和系统免疫的详细成分，并确定这些因素中的哪一种可以驱动病变的发展或/和寄生虫的控制。这些结果还将提供重要的数据，将增加对利什曼原虫免疫的了解，为观察到的皮肤和粘膜利什曼病患者的病理差异提供解释，并有助于改进未来疫苗和药物靶点的设计。

Parasites belonging to the genus Leishmania are among the most diverse of human pathogens, both in terms of geographical distribution and in the variety of clinical syndromes caused by them. Currently, 12 million people are infected worldwide in 88 tropical/subtropical countries, 2 million new infections are reported annually, and 350 million people are under infection risk. In the past decade, the number of cases in endemic areas has increased sharply. In addition, leishmaniasis is spreading to several non-endemic areas of the world due to coinfections with HIV. Control measures currently available are case detection and treatment with drugs, which are expensive, not always available and cannot be self-administered. The problem is further aggravated by the surge of drug resistance parasites necessitating the development of an anti-Leishmania vaccine or other immunological therapies urgent. Research has demonstrated the importance of the immunity in controlling both cutaneous and mucocotaneous leishmaniasis, however the majority of this work has been performed on blood samples taken from patients and not from the site of infection at the skin. In this context, the current project aims to characterize the immune mechanisms involved in controlling Leishmania in both the blood and the skin. In this proposal, we aim to apply this established approach for the first time in studies with human localized cutaneous (LCL) and mucocutaneous leishmaniasis (MCL) in order to understand the immune mechanisms associated to cell development, function and regulation in the skin and blood. Through this work we will be able to identify in detail components of the cutaneous and systemic immunity that are involved during infection and determine which of these factor can drive lesion development or/and parasite control. The results will also provide important data that will increase the understanding of Leishmania immunity providing explanations about pathological differences observed in cutaneous and mucocotaneous leishmaniasis patients and contribute to the improved design of future vaccines and drug target.