Innate and adaptive immune responses to Leishmania

对利什曼原虫的先天和适应性免疫反应

• 批准号: 7575822
• 负责人: DAVID M MOSSER
• 金额: $ 31.08万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575822
• 关键词: Address; Affect; Antibodies; Antibody Formation; Antigen-Antibody Complex; Antigen-Presenting Cells; Back; C57BL/6 Mouse; CD40 Ligand; Cell Culture Techniques; Complex; Dendritic Cells; Disease Progression; Growth; Immune; Immune response; Immunoglobulin G; Inbred BALB C Mice; Infection; Interleukin-10; Invaded; Lead; Leishmania; Leukocytes; Ligands; Ligation; Measures; Mus; NF-kappa B; Natural Immunity; Nature; Organism; Parasites; Pathogenesis; Predisposition; Process; Production; Resistance; Role; Surface; T-Cell Activation; T-Lymphocyte; Testing; Toll-like receptors; Transgenic Organisms; Virulence; Work; base; chemokine; cytokine; macrophage; pathogen; receptor; response

DESCRIPTION (provided by the applicant): This proposal seeks to test the hypothesis that the intracellular protozoan, Leishmania spp., is able to manipulate both the innate and the adaptive immune response of the host to their advantage. We propose that promastigotes are infectious because they evade the innate immune response. We also propose that amastigotes are infectious because they exploit the adaptive immune response. The first aim of the proposal will examine innate immune activation by Leishmania promastigotes. This aim is built on the observation that Leishmania promastigotes infect leukocytes by a process that fails to induce the production of cytokines and co-stimulatory molecules. This led us to hypothesize that Leishmania promastigotes fail to interact with TLRs, and as a consequence fail to translocate NF-kappaB in macrophages and dendritic cells. The main question that we will ask in Aim 1 is whether this quiescent mechanism of entry is a critical component of parasite virulence. To address this question, we have developed transgenic Leishmania parasites that express TLR activators on their surface. We will measure the infectivity of these transgenic organisms in mice and in cell cultures. The second aim of this proposal is based on our observation that mice lacking the heavy chain of IgG (JH mice) are resistant to L. major infections despite being on a BALB/c background. We have also observed that the addition of anti-Leishmania IgG to these mice reverts them back to being susceptible to L. major infections. In the second aim of this proposal, we plan to determine how IgG can work to the detriment of the host infected with an intracellular pathogen. We will determine the role of IL-10 in this process, and specifically the role of APC-derived IL-10 as an IgG-induced permissive factor. These studies pertain directly to the pathogenesis of Leishmania infection. They may also provide important basic information about the role of antibody during infections with intracellulars, and about the ability of APCs to influence the nature of an adaptive immune response.

描述（由申请人提供）：该提案旨在检验细胞内原生动物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的假设。我们认为前鞭毛体具有传染性，因为它们逃避先天免疫反应。我们还认为无鞭毛体具有传染性，因为它们利用适应性免疫反应。该提案的第一个目标是检查利什曼原虫前鞭毛体的先天免疫激活。这一目标是建立在利什曼原虫前鞭毛体通过无法诱导细胞因子和共刺激分子产生的过程感染白细胞的观察基础上的。这使我们推测利什曼原虫前鞭毛体无法与 TLR 相互作用，因此无法在巨噬细胞和树突细胞中易位 NF-κB。我们在目标 1 中要问的主要问题是这种静止的进入机制是否是寄生虫毒力的关键组成部分。为了解决这个问题，我们开发了转基因利什曼原虫寄生虫，其表面表达 TLR 激活剂。我们将测量这些转基因生物在小鼠和细胞培养物中的感染性。该提案的第二个目标是基于我们的观察，即缺乏 IgG 重链的小鼠（JH 小鼠）尽管处于 BALB/c 背景，但仍能抵抗重大利斯特菌感染。我们还观察到，向这些小鼠添加抗利什曼原虫 IgG 可使它们恢复到对重大利什曼原虫感染的易感性。在该提案的第二个目标中，我们计划确定 IgG 如何对感染细胞内病原体的宿主造成损害。我们将确定 IL-10 在此过程中的作用，特别是 APC 衍生的 IL-10 作为 IgG 诱导的许可因子的作用。这些研究直接涉及利什曼原虫感染的发病机制。它们还可以提供有关抗体在细胞内感染过程中的作用以及 APC 影响适应性免疫反应性质的能力的重要基本信息。