Pathogenic Mechanisms of Cutaneous Leishmaniasis

皮肤利什曼病的发病机制

• 批准号: 7920778
• 负责人: LYNN SOONG
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920778
• 关键词: Accounting; Address; Adoptive Transfer; American Leishmaniasis; Antigens; Area; Biological; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cellular Immunity; Chronic; Coculture Techniques; Comparative Study; Complex; Cutaneous; Cutaneous Leishmaniasis; Defect; Dendritic Cells; Dendritic cell activation; Diffuse Cutaneous Leishmaniasis; Disease; Disease Outcome; Effector Cell; Epitopes; Equilibrium; Failure; Funding; Gene Targeting; Generations; Genetic; Goals; Healed; Host Defense; Human; IL2RA gene; Immune response; Immune system; Immunity; Immunization; Immunologic Deficiency Syndromes; Impairment; In Vitro; Inbred BALB C Mice; Inbred Strains Mice; Infection; Infection Control; Integration Host Factors; Interferon Type II; Interleukin-10; Interleukin-4; Knockout Mice; Knowledge; Leishmania; Leishmaniasis; Lesion; Ligands; Link; Mediating; Modeling; Molecular; Mouse Strains; Mus; Parasites; Pathogenesis; Phenotype; Predisposition; Preventive Intervention; Process; Proteins; Research; Research Personnel; Role; Saliva; Sand Flies; Solid; Staging; Stimulus; Surrogate Markers; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Toll-like receptors; Treatment Efficacy; Treatment Protocols; Vaccines; Work; base; chemokine; cytokine; design; disorder control; healing; immunogenic; novel; prevent; response; stem; therapy design

DESCRIPTION (provided by applicant): Infection with Leishmania amazonensis (La) can cause diverse forms of leishmaniasis in humans in the New World, and results in non-healing cutaneous lesions in most inbred mouse strains. Host factors responsible for this generalized susceptibility are poorly understood; however, it is clear that control of this infection relies on the induction of a strong Th1-type immune response. Evidence generated during the previous funding period has highlighted unique aspects of host-parasite interaction, and supports a novel hypothesis that this parasite not only suppresses activation of innate and Th1 responses via an IL-4-independent mechanism, but also takes advantage of the adaptive immune system for its propagation and persistence. This application is to seek continued support in three specific areas of research that are cohesively linked. First, we will examine whether susceptibility to La infection is due to defects at the level of dendritic cells (DC) via alteration of their antigen-presenting functions. Comparative studies will be conducted using a mouse strain that gives rise to different disease outcomes following infection with La and L. major. Secondly, we will focus on the La infection model and examine the impact of DC-stimulating agents on parasite-specific immunity and disease outcome. Studies employing cytokines, chemokines, and ligands for Toll-like receptors (TLR) will provide a mechanistic explanation of defects in La-infected DCs. Finally, we will examine the mechanisms and potential of modulating regulatory T cells for the control of La infection in naive and immunized mice. Approaches will include cell depletion prior to treatment/immunization and adoptive transfer of traceable cells to wild-type or gene-targeted knockout mice. Completion of this proposed study will aid in designing new control strategies for Leishmania and other chronic infections for which therapeutic/preventive interventions are not available.

描述（由申请方提供）：亚马逊利什曼原虫（La）感染可在新世界人类中引起多种形式的利什曼病，并导致大多数近交系小鼠品系的皮肤损伤无法愈合。负责这种广义的易感性的宿主因素知之甚少，但是，很明显，这种感染的控制依赖于诱导一个强大的Th 1型免疫反应。在上一个资助期间产生的证据突出了宿主-寄生虫相互作用的独特方面，并支持一种新的假设，即这种寄生虫不仅通过IL-4非依赖性机制抑制先天性和Th 1应答的激活，而且还利用适应性免疫系统进行繁殖和持久性。这个应用程序是寻求在三个具体的研究领域是紧密相连的持续支持。首先，我们将研究是否La感染的易感性是由于缺陷的树突状细胞（DC）通过改变其抗原呈递功能的水平。将使用感染La和L后引起不同疾病结果的小鼠品系进行比较研究。少校其次，我们将专注于La感染模型，并检查DC刺激剂对寄生虫特异性免疫和疾病结果的影响。采用细胞因子、趋化因子和Toll样受体（TLR）配体的研究将为La感染的DC中的缺陷提供机制解释。最后，我们将研究机制和潜力的调节T细胞的控制La感染的幼稚和免疫小鼠。方法将包括治疗/免疫前的细胞耗竭和将可追踪细胞过继转移至野生型或基因靶向敲除小鼠。这项拟议研究的完成将有助于为利什曼原虫和其他慢性感染设计新的控制策略，这些慢性感染无法进行治疗/预防干预。