Innate and adaptive immune responses to Leishmania

这一建议的中心假设是利什曼原虫。能够操纵宿主的先天免疫反应和获得性免疫反应，使之成为自己的优势。该提案的第一个目标是关注利什曼原虫操纵先天免疫反应的能力，第二个目标是关注寄生虫操纵适应性免疫反应的能力。这项提议是建立在实验室中两个独立的、令人惊讶的观察结果之上的。该提案的第一个目的是建立在观察到巨噬细胞和DC感染利什曼原虫前鞭毛体未能诱导细胞因子产生或APC成熟的基础上。因此，我们假设利什曼原虫不能参与宿主的先天免疫反应。我们将在目标1中提出的主要问题是，未能激活先天免疫是否是一个关键问题 成分对寄生虫的致病力。为了提出这个问题，我们开发了转基因利什曼原虫，它确实能与巨噬细胞和DC上的Toll样受体(TLRs)结合。我们计划研究这些生物的生物学，并确定它们是否以不同的方式呈现给T细胞，它们是否会引起与野生型生物不同的损伤，以及它们是否会在质量和数量上引发不同的适应性免疫反应。第二个目的是基于观察到缺乏重链免疫球蛋白的小鼠(JH小鼠)对主要乳杆菌感染具有抵抗力，尽管它们是BALB/c易感背景。向这些小鼠体内注入免疫血清实际上会增加病变进展和寄生虫复制。 我们计划确定免疫球蛋白是如何对感染了细胞内寄生虫的宿主有害的。我们假设免疫球蛋白导致APC产生IL-10，我们将确定APC衍生的IL-10对该生物体的适应性免疫反应的影响程度。我们将确定免疫球蛋白免疫复合体的存在会改变适应性免疫反应的哪些方面。这些研究不仅直接与利什曼原虫的免疫有关，还可能提供关于细胞内病原体的免疫共振以及APC在调节适应性免疫反应中的作用的基本信息。

The central hypothesis of this proposal is that Leishmania spp. are able to manipulate both the innate and the adaptive immune responses of the host to their advantage. The first aim of the proposal focuses on the ability of Leishmania to manipulate the innate immune response, and the second aim focuses on the ability of the parasite to manipulate the adaptive immune response. The proposal is built on two separate and surprising observations that were made in the lab. The first aim of the proposal is built on the observation that infection of macrophages and DC with Leishmania promastigotes fails to induce cytokine production or APC maturation. Thus we hypothesized that Leishmania fail to engage the innate immune responses of the host. The main question we will ask in Aim 1 is whether this failure to activate innate immunity is a critical component to parasite virulence. To ask this question, we have developed transgenic Leishmania that do engage Toll-Like Receptors (TLRs) on macrophages and DC. We plan to study the biology of these organisms and determine whether they are presented to T cells differently, whether they cause lesions that are different from wild-type organisms, and whether they induce qualitatively and quantitatively different adaptive immune responses. The second aim is based on the observation that mice lacking the heavy chain of IgG (JH mice) are resistant to L. major infection, despite being on the susceptible BALB/c background. The infusion of immune serum into these mice actually increases lesion progression and parasite replication. We plan to determine how IgG can work to the detriment of the host infected with an intracellular parasite. We hypothesize that IgG leads to IL-10 production by APCs, and we will determine the extent to which APCderived IL-10 influences adaptive immune responses to this organism. We will determine which aspects of the adaptive immune response are altered by the presence of IgG immune complexes. These studies not only pertain directly to Leishmania immunity, but they may also provide basic general information about theimmune resonse to intracellular pathogens, and about the role of APCs in modulating adaptive immune responses.