Parasite polymorphism and host immune response in cutaneous leishmaniasis outcome

摘要 巴西利什曼原虫感染可引起高光谱的临床表现，包括 流行形式为皮肤利什曼病(CL)。炎症反应是CL的一个标志，高水平的 肿瘤坏死因子、CD8+T细胞和单核巨噬细胞与皮肤溃疡的发生 这些人。在我们的流行区，我们已经能够识别出非溃烂病变的个体。 (丘疹)，局部淋巴结病，利什曼原虫皮肤试验阳性。这些人报告的人数少于 疾病进展15天，被认为是早期CL(ECL)。我们的初步数据显示，ECL 患者比CL患者有更多的寄生虫，并能够对利什曼原虫产生炎症反应 体外试验中的抗原。巴西钩端螺旋体传播地区的一个主要问题是治疗失败。 我们小组和其他人的研究表明，高达30%的CL(伴有溃烂病变)患者未能通过 五价锑，巴西卫生部长治疗利什曼病的首选药物。早期治疗 大多数传染病使患者受益，缩短了治愈和复发的时间。然而，我们 有报道称，ECL的治疗失败率高达70%。有趣的是，我们的初步数据显示 从ECL和CL分离的大多数寄生虫的遗传差异。我们的主要假设是 ECL治疗失败率高与耐药性和缺乏对 由于大量利什曼原虫引起的炎症，从而促进溃疡的发展。为了调查 与治疗失败相关的机制我们将建立一组纳入ECL和CL患者的队列 在我们疫区的卫生站。在本提案的目标1中，我们打算评估寄生虫 基因多态和利什曼杀毒药物耐药性，以及宿主和利什曼原虫基因的量化 与治疗失败有关。在目标2中，我们将研究与治疗有关的免疫机制。 失败了。为此，我们将确定细胞、可溶性因子、细胞受体和调节因子的作用 治疗前和治疗中ECL和CL的机制。在目标3中，我们将研究二十烷类化合物的能力。 Omega-3脂肪酸代谢产物(DHA、EPA和Resolvins)调节ECL和 克莱。及早识别治疗失败的个体将允许及早使用另一种选择 心理治疗。

Summary Leishmania braziliensis infection may cause a high spectrum of clinical manifestation, including the more prevalent form, cutaneous leishmaniasis (CL). Inflammatory response is a hallmark of CL and high levels of TNF, presence of CD8+ T cells and mononuclear phagocytes are associated with skin ulcer development in these individuals. In our endemic area we have been able to identify individuals with a non-ulcerated lesion (papule), with regional lymphadenopathy and positive Leishmania skin test. These individuals report less than 15 days of disease evolution and are considered to have early CL (ECL). Our preliminary data shows that ECL patients have more parasites than CL ones and are able to mount inflammatory response to Leishmania antigen in in-vitro assays. A major problem in areas of L. braziliensis transmission regards therapeutic failure. Studies from our group and others show that up to 30% of CL (with ulcerated lesion) patients fail treatment with pentavalent antimony, drug of choice of Brazilian Minister of Health to treat leishmaniasis. The early treatment of the majority of infectious disease benefits the patients, decreasing time to cure and relapses. However, we have been reporting that in ECL the therapeutic failure is up to 70%. Interestingly, our preliminary data show genetic differences between most parasites isolated from ECL and those from CL. Our main hypothesis is that high rates of therapeutic failure in ECL is associated with drug resistance and lack of regulation of inflammatory due to high amounts of Leishmania, thus contributing to ulcer development. To investigate the mechanisms associated with therapeutic failure we will establish a cohort of ECL and CL individuals admitted in the health post of our endemic area. In the Aim 1 of the present proposal we intend to assess parasite genetic polymorphism and resistance to leishmanicidal drugs, and quantify host and Leishmania genes associated with therapeutic failure. In Aim 2 we will investigate immune mechanisms involved of therapeutic failure. For that we will determine the contribution of cells, soluble factors, cell receptors and regulatory mechanisms in ECL and CL before and during therapy. In Aim 3 we will study the ability of eicosanoids metabolites of Omega-3 fatty acids (DHA, EPA and Resolvins) to regulate inflammatory response in ECL and CL. The early identification of individuals that will fail treatment will allow the early use of another choice of therapy.