Genetic and Environmental Determinants of Symptomatic and Asymptomatic Leishmani

利什曼病包括具有不同临床结果的复杂疾病，包括局部或局部性利什曼病。 广泛的皮肤、粘膜和内脏综合征。大多数感染利什曼原虫的人 控制感染并保持无症状。然而，控制感染的机制， 是否有寄生虫清除尚不清楚。美国表皮利什曼病（ATL）由L。 巴西人进化为对寄生虫抗原有偏向的免疫应答，表现为高TNF α和INF γ 但IL-10低。相比之下，内脏利什曼病（VL）表现为高水平的IL-10和TNF α，而低水平的IL-10和TNF α。 INFy的水平。在最近的研究中，我们已经表明，IL 6和控制伤口愈合反应的基因座， 与皮肤利什曼病相关，HLA与L. I.恰加斯 感染我们假设利什曼原虫感染的临床谱是由免疫系统决定的。 在感染部位局部调节并反映在外周的反应，提供了潜在的 疾病进展或恢复的生物标志物。这项建议的主要重点是解决 不同种类利什曼原虫和人类宿主感染的结果之间的对比 应答我们建议研究受主要遗传因素影响的基因表达的新途径， 风险因素，使我们能够进一步识别将预测疾病结果的特征， 可在临床上应用于疾病的管理或预防。本研究的主要目的是：（1） 确定宿主基因调控的下游途径，这些基因通过以下途径影响VL和ATL： 感染组织和外周血的转录谱;（2）了解功能相关性 IL 6和FLU在ATL中的表观遗传学调控;（3）探讨ATL的免疫学机制 确定了L. I.查加斯感染，并确定是否在宿主中的变异性 对利什曼原虫抗原的免疫应答是由于HLA。这些研究将提供有关新的 通过描述导致寄生虫控制和清除的机制， 并通过识别血液或感染组织中可以作为目标的分子特征。

Leishmaniasis encompasses a complex of diseases with diverse clinical outcomes that include localized or widespread cutaneous, mucosal and visceral syndromes. The majority of people infected with Leishmania control infection and remains asymptomatic. However, the mechanisms that medicate control infection and whether there is parasite clearance are not known. American tegumentary leishmaniasis (ATL) due to L. braziliensis evolves with a biased immune response to parasite antigens manifested by high TNFa and INFy but low IL-10. In contrast, visceral leishmaniasis (VL) presents with high levels of IL-10 and TNFa and low levels of INFy. In recent studies we have shown that IL6 and loci controlling the wound healing response are associated with tegumentary leishmaniasis, and that HLA is associated with the outcome of L. i. chagasi infection. We hypothesize that the clinical spectrum of Leishmania infections is determined by immune responses regulated locally at the site of infection and reflected in the periphery, providing potential biomarkers for disease progression or recovery. Major emphases of this proposal will be address the contrasts between the outcomes of infection with different species of Leishmania and the human host responses. We propose to study novel pathways of gene expression that are influenced by major genetic risk factors, allowing us to progress to the identification of signatures that will predict disease outcome that can be applied clinically in the management or prevention of disease. The major goals of this study are: (1) To determine the downstream pathways regulated by host genes shown to influence VL and ATL through transcriptional profiling of infected tissues and peripheral blood; (2) To understand the functional correlates and epigenetic regulation of IL6 and FLU in ATL; and (3) To identify the immunologic mechanisms determining the different phenotypes in L. i. chagasi-infection and to define whether variability in host immune response to Leishmania antigens is due to HLA. These studies will provide infonmation about novel targets for therapeutic intervention by delineating the mechanisms that lead to parasite control and clearance and by identifying molecular signatures in the blood or infected tissues that can be targeted.