Innate and adaptive immune responses to Leishmania

描述（由申请人提供）：本提案旨在检验细胞内原生动物利什曼原虫属，能够操纵宿主的先天性和适应性免疫反应，使其对自己有利。我们认为前鞭毛体具有传染性是因为它们逃避了先天免疫反应。我们还提出，无鞭毛体是传染性的，因为他们利用适应性免疫反应。该提案的第一个目的将检查利什曼原虫前鞭毛体的先天免疫激活。这一目的是建立在利什曼原虫前鞭毛体通过不能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。这使我们假设利什曼原虫前鞭毛体不能与TLR相互作用，因此不能在巨噬细胞和树突状细胞中转运NF-κ B。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，我们已经开发了转基因利什曼原虫，表达TLR激活剂在其表面上。我们将测量这些转基因生物在小鼠和细胞培养中的感染性。该建议的第二个目的是基于我们的观察，即缺乏IgG重链的小鼠（JH小鼠）对L.尽管是在BALB/c背景下，但仍存在严重感染。我们还观察到，向这些小鼠中加入抗利什曼原虫IgG使它们恢复对利什曼原虫的敏感性。严重感染。在本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起损害作用。我们将确定IL-10在这一过程中的作用，特别是APC衍生的IL-10作为IgG诱导的容许因子的作用。这些研究直接涉及利什曼原虫感染的发病机制。它们还可以提供关于抗体在细胞内感染期间的作用以及关于APC影响适应性免疫应答的性质的能力的重要基本信息。

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.