Pathogenic Mechanisms of Cutaneous Leishmaniasis

描述（由申请人提供）：亚马逊利什曼原虫（La）感染可在新大陆的人类中引起多种形式的利什曼病，并在大多数近交小鼠品系中导致不可愈合的皮肤病变。导致这种普遍易感性的宿主因素了解甚少；然而，很明显，这种感染的控制依赖于诱导强烈的th1型免疫反应。在之前的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，并支持了一种新的假设，即这种寄生虫不仅通过il -4独立机制抑制先天和Th1反应的激活，而且还利用适应性免疫系统进行繁殖和持久性。这个申请是为了在三个紧密相连的特定研究领域寻求持续的支持。首先，我们将研究对La感染的易感性是否由于树突状细胞（DC）水平上的缺陷，通过改变它们的抗原呈递功能。比较研究将使用一种小鼠品系进行，该品系在感染La和L. major后会产生不同的疾病结果。其次，我们将重点关注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局的影响。利用细胞因子、趋化因子和toll样受体（TLR）配体的研究将为la感染dc的缺陷提供机制解释。最后，我们将研究调节调节性T细胞控制幼年和免疫小鼠La感染的机制和潜力。方法将包括治疗/免疫前的细胞消耗和可追踪细胞过继转移到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无法获得治疗/预防干预措施的慢性感染设计新的控制策略。

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.