Genetic and Environmental Determinants of Symptomatic and Asymptomatic Leishmaniasis

利什曼病包括一组复杂的疾病，具有不同的临床结果，包括局部性或 广泛存在的皮肤、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，药物控制感染和 目前尚不清楚是否有寄生虫清除。美国被盖型利什曼病(ATL)由L. 巴西种对寄生虫抗原的免疫应答偏向，表现为高肿瘤坏死因子α和干扰素γ 但IL-10水平较低。相反，内脏利什曼病(VL)表现为高水平的IL-10和肿瘤坏死因子α和低水平的 干扰素γ水平。在最近的研究中，我们发现控制伤口愈合反应的IL6和基因座是 与被盖型利什曼病相关，且人类白细胞抗原与查格斯病的转归有关 感染。我们假设利什曼原虫感染的临床谱系是由免疫决定的。 在感染部位局部调节的反应，并反映在外围，提供潜在的 疾病进展或恢复的生物标志物。这项提案的主要重点将是 不同种类利什曼原虫与人类宿主感染结局的对比 回应。我们建议研究受主要基因影响的基因表达的新途径。 风险因素，使我们能够进步到识别将预测疾病结果的标志 可在临床上用于疾病的管理或预防。本研究的主要目标是：(1) 确定受宿主基因调控的下游通路通过以下途径影响VL和ATL 感染组织和外周血的转录图谱；(2)了解功能相关 以及IL6和Flu在ATL中的表观遗传调控；以及(3)确定其免疫机制 检测查格西李氏杆菌感染的不同表型，并确定宿主是否存在变异性 对利什曼原虫的免疫应答是由人类白细胞抗原引起的。这些研究将为小说研究提供信息 通过描述导致寄生虫控制和清除的机制来进行治疗干预的目标 并通过识别血液或受感染组织中可以成为靶点的分子特征。

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 TNFα and INFγ but low IL-10. In contrast, visceral leishmaniasis (VL) presents with high levels of IL-10 and TNFα and low levels of INFγ. 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.