Parasite polymorphism and host immune response in cutaneous leishmaniasis outcome

皮肤利什曼病结果中的寄生虫多态性和宿主免疫反应

• 批准号: 10092917
• 负责人: Lucas P Carvalho
• 金额: $ 11.85万
• 依托单位: FEDERAL UNIVERSITY OF BAHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-20 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092917
• 关键词: Antigens; Antimony; Appearance; Area; Blood; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Cells; Chromosomes; Clinical; Communicable Diseases; Cutaneous Leishmaniasis; Data; Development; Dinoprostone; Disease; Disease Progression; Down-Regulation; Drug resistance; Early identification; Early treatment; Eicosanoids; Enlargement of lymph nodes; Enzymes; Evolution; Exhibits; Failure; Genes; Genetic; Genetic Polymorphism; Genotype; Granuloma; Haplotypes; Health; Hypersensitivity skin testing; Immune; Immune response; Impairment; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-1 beta; Leishmania; Leishmania braziliensis; Leishmaniasis; Lesion; Leukotriene B4; Leukotrienes; Lymphocyte; Measures; Mediating; Mononuclear; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Parasite resistance; Parasites; Patients; Peripheral Blood Mononuclear Cell; Phagocytes; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Positioning Attribute; Predisposition; Production; Property; Prostaglandin Production; Prostaglandins; Receptor Cell; Regulation; Relapse; Reporting; Resistance; Role; Serum; Severity of illness; Site; Source; TNF gene; Testing; Therapeutic; Time; Tissues; Treatment Failure; Ulcer; base; chemokine; cohort; cytokine; draining lymph node; experimental study; genetic resistance; genomic locus; immunoregulation; in vitro Assay; inflammatory milieu; lymphadenopathy; macrophage; prevent; recruit; skin ulcer; transmission process

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.

总结 巴西利什曼原虫感染可引起高谱的临床表现，包括更多的 流行形式，皮肤利什曼病（CL）。炎症反应是CL的标志，高水平的炎症反应是CL的特征。 肿瘤坏死因子、CD 8 + T细胞和单核吞噬细胞的存在与皮肤溃疡的发展有关， 这些人。在我们的流行区，我们已经能够确定个人与非溃疡病变 （丘疹），伴局部淋巴结病和利什曼原虫皮肤试验阳性。这些人报告说， 15天的疾病进展，并被认为有早期CL（ECL）。我们的初步数据显示， 患者比CL患者有更多的寄生虫，并且能够对利什曼原虫产生炎症反应 抗原在体外测定中。L.巴西人的传播与治疗失败有关。 我们小组和其他人的研究表明，高达30%的CL（溃疡病变）患者治疗失败， 五价锑，巴西卫生部长治疗利什曼病的首选药物。早期治疗 大多数传染病的治疗有益于患者，减少了治愈和复发的时间。但我们 据报道，在ECL中，治疗失败率高达70%。有趣的是，我们的初步数据显示 ECL和CL分离的大多数寄生虫之间存在遗传差异。我们的主要假设是 ECL治疗失败率较高与耐药性和缺乏对 由于大量的利什曼原虫引起的炎症，因此有助于溃疡的发展。探讨 我们将建立一个ECL和CL患者队列， 在我们流行地区的卫生站。在本提案的目标1中，我们打算评估寄生虫 遗传多态性和对杀利什曼原虫药物的抗性，并量化宿主和利什曼原虫基因 与治疗失败有关。在目标2中，我们将研究治疗性免疫相关的免疫机制。 失败为此，我们将确定细胞，可溶性因子，细胞受体和调节因子的作用。 治疗前和治疗期间ECL和CL的机制。在目标3中，我们将研究类二十烷酸的能力， Omega-3脂肪酸的代谢物（DHA、EPA和Resolvins）调节ECL中的炎症反应， CL.早期识别治疗失败的个体将允许早期使用另一种选择， 疗法