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Innate and adaptive immune responses to Leishmania

对利什曼原虫的先天和适应性免疫反应

基本信息

批准号：
6777245
负责人：
DAVID M MOSSER
金额：
$ 33.41万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2005-04-30
项目状态：
已结题

项目摘要

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.

该提案的中心假设是利什曼原虫。能够操纵宿主的先天性和适应性免疫反应以发挥其优势。该提案的第一个目标侧重于利什曼原虫操纵先天免疫反应的能力，第二个目标侧重于寄生虫操纵适应性免疫反应的能力。该提议建立在实验室中进行的两个独立且令人惊讶的观察结果之上。该提案的第一个目标是建立在利什曼原虫前鞭毛体感染巨噬细胞和 DC 无法诱导细胞因子产生或 APC 成熟的观察基础上的。因此，我们假设利什曼原虫无法参与宿主的先天免疫反应。我们在目标 1 中要问的主要问题是，激活先天免疫的失败是否是一个关键问题？寄生虫毒力的组成部分。为了提出这个问题，我们开发了转基因利什曼原虫，它确实与巨噬细胞和 DC 上的 Toll 样受体 (TLR) 结合。我们计划研究这些生物体的生物学，并确定它们是否以不同的方式呈递给 T 细胞，它们是否引起与野生型生物体不同的病变，以及它们是否诱导定性和定量不同的适应性免疫反应。第二个目标是基于以下观察结果：缺乏 IgG 重链的小鼠（JH 小鼠）尽管处于易感 BALB/c 背景下，但对硕大利斯特菌感染有抵抗力。将免疫血清输注到这些小鼠体内实际上会增加病变进展和寄生虫复制。我们计划确定 IgG 如何对感染细胞内寄生虫的宿主造成损害。我们假设 IgG 导致 APC 产生 IL-10，并且我们将确定 APC 衍生的 IL-10 在多大程度上影响对该生物体的适应性免疫反应。我们将确定 IgG 免疫复合物的存在会改变适应性免疫反应的哪些方面。这些研究不仅直接涉及利什曼原虫免疫，而且还可能提供有关细胞内病原体免疫反应以及 APC 在调节适应性免疫反应中的作用的基本一般信息。