Senescent CD8+ T and NK cells contribute to immunopathogy duting cutaneous 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。研究表明，免疫在控制皮肤和粘膜皮肤利什曼病方面的重要性，但在感染部位发展的严重皮肤损害主要是由于非特异性组织损伤，但原因尚不清楚。这项工作的大部分是从患者身上采集的血液样本，而不是从皮肤感染部位采集的血液样本。在这种情况下，当前提案的一个独特之处是，我们将调查从皮损和非皮损部位采集的相同患者的血液和皮肤。这项拨款申请的主要假设是，感染者皮肤免疫病理的严重程度是由于两种免疫细胞--自然杀伤(NK)细胞和代表免疫系统“爸爸的军队”的一种T细胞--介导的非特异性损伤。这两种类型的细胞可能都不是由皮肤病变中的寄生虫触发的，而是识别未感染的皮肤细胞中的诱饵分子，导致它们被摧毁。这会导致大的皮肤损伤，其中包含很少的寄生虫，但有大量危险的白细胞。在这项研究中，我们将调查患者皮损中白细胞的性质。我们将识别促进非特异性组织损伤的诱骗受体。我们还将研究在皮肤中被激活的广泛的基因，以确定免疫系统和皮肤之间的相互作用是如何组织的线索。我们还将识别一些基因，这些基因将为我们提供线索，说明可能正在发生哪些其他过程，而这些过程不允许病变消失。在这项研究的其他部分，我们将通过在试管中培养皮肤细胞来模拟它们之间的相互作用，以探测它们的相互作用，并找到阻止它们的方法。最后，我们将调查一种被称为Sestrins的触发分子的参与，我们之前已经证明，Sestrins参与了建立可能导致皮肤利什曼病患者皮肤损伤形成的诱骗机制。作为这项提议的附加值，圣埃斯皮里托联邦大学将提供1名技术人员和1名博士生来研究这项拨款的各个方面。

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 mucocutaneous leishmaniasis, however the severe skin lesions that develop at the infected site is largely due to non-specific tissue damage but the reasons for this are unclear. 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, a unique feature of the current proposal is that we will be investigating the blood as well as the skin from the same patients, taken from both lesional and non-lesional sites. The main hypothesis of this grant application is that the severity of cutaneous immunopathology in infected individuals is due to non-specific damage mediated by both two types of immune cell namely the natural killer (NK) cells and a type of T cell that represent the "Dad's Army" of the immune system. Both these cell types are probably not triggered by the parasite in the skin lesions, instead they recognize decoy molecules in non-infected skin cells that cause them to be destroyed. This results in the large skin lesions that contain few parasites but huge numbers of dangerous white cells. In this study we will investigate the nature of the white cells in the skin lesions of patients. We will identify the decoy receptors that promote the non-specific tissue damage. We will also look at the wide array of genes that are activated in the skin to identify clue of how the interactions between the immune system and the skin are organized. We will also identify genes that will give us clues as to what other processes may be occurring that do not allow the lesions to resolve. In other parts of the study we will mimic the interaction of cell that are in the skin by growing them in a test tube to probe their interactions and find a way to block them. Finally we will investigate the involvement of a set off molecules known as sestrins, that we previously showed were involved in setting up the decoy mechanisms that may lead to skin lesion formation in patients with cutaneous leishmaniasis.As added value to this proposal, The Federal University of Espirito Santo will contribute 1 Technician and 1 PhD student to work on aspects of this grant.