Regulation of innate immunity to infection

对感染的先天免疫的调节

• 批准号: 6815409
• 负责人: Lawrence L. Johnson
• 金额: $ 35万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815409
• 关键词: CD28 molecule; T lymphocyte; Toxoplasma gondii; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; heme oxygenase; immune response; immunity; immunoregulation; indoleamine; interleukin 10; laboratory mouse; microorganism immunology; natural killer cells; neutrophil; oxygenases; toxoplasmosis; transforming growth factors

DESCRIPTION (provided by the applicant): This proposal will examine the regulation of innate immunity, using infection of mice with the NIAID Category B Priority Pathogen, Toxoplasma gondii, as a model system. Our prior studies have established an important protective role for innate immunity in T. gondii infection, but little is known about its regulation. In contrast, current studies have revealed important features regarding regulation of acquired immunity. In several models, acquired T cell-dependent immunity has been found to be regulated by inhibitory CD4+CD25 + T cells (Treg) that mediate their effects via IL-10, CTLA-4, and/or TGF-beta. T cell-dependent immunity can also be regulated by catabolites produced as a result of induction of the enzymes indoleamine-2,3-dioxygenase (IDO) and heme oxygenase (HO). Our preliminary studies show that IL-10, TGF-beta, IDO and HO mRNAs are induced in several organs during acute T. gondii infection. In this proposal, we will test the hypothesis that Treg cells, the cytokines they produce, and the enzymes IDO and HO are significant regulators of NK cell- and neutrophil-dependent innate immunity to T. gondii. Thus, these studies will determine whether components of innate resistance to infection are regulated, or can be regulated, by any of several likely cellular and molecular candidates. The consequences of regulation will be determined at the cellular and molecular level. Elucidation of the mechanistic basis of regulation of innate immunity will lead to a fuller understanding of resistance to acute infection. Moreover, innate immunity significantly affects the generation of acquired immunity to many infections. Thus, the proposed studies will form a foundation on which to build future studies to examine how regulation of innate immunity impacts acquired immunity to infection and vaccination.

描述（由申请人提供）：该提案将使用具有NIAID类别B优先病原体Toxoplasma Gondii作为模型系统的小鼠的感染来检查先天免疫的调节。我们先前的研究已经确定了弓形虫感染中先天免疫的重要保护作用，但对其调节知之甚少。相比之下，当前的研究揭示了有关获得免疫的重要特征。在几种模型中，发现获得的T细胞依赖性免疫受抑制性CD4 + CD25 + T细胞（Treg）调节，这些抑制性CD4 + CD25 + T细胞（Treg）通过IL-10，CTLA-4和/或TGF-BETA介导其作用。 T细胞依赖性免疫也可以受到诱导酶 - 吲哚胺-2,3-二加氧酶（IDO）和血红素加氧酶（HO）的诱导产生的分解代谢产物的调节。我们的初步研究表明，在急性T. gondii感染期间，在多个器官中诱导IL-10，TGF-beta，IDO和HO mRNA。在此提案中，我们将检验以下假设：Treg细胞，它们产生的细胞因子以及IDO和HO酶是NK细胞和中性粒细胞依赖性的先天性免疫的重要调节剂。因此，这些研究将确定是否由几个可能的细胞和分子候选者中的任何一个调节先天抵抗感染的成分，或者可以受到调节。调节的后果将在细胞和分子水平上确定。阐明先天免疫调节的机理基础将使人们对急性感染的抗性有更深入的了解。此外，先天免疫会显着影响对许多感染的获得免疫的产生。因此，拟议的研究将构成建立未来研究的基础，以研究先天免疫的调节如何影响获得的免疫对感染和疫苗接种。