Innate immunity and Salmonella pathogenesis

先天免疫和沙门氏菌发病机制

• 批准号: 8478572
• 负责人: Gregory M Barton
• 金额: $ 32.99万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478572
• 关键词: Alleles; Animals; Backcrossings; Cells; Dependence; Disease; Disease Outbreaks; Environment; Foundations; Generations; Genes; Gentamicins; Goals; Grant; Growth; Image; Immune system; Inbred Strains Mice; Intestines; Knock-in Mouse; Manuscripts; Masks; Measures; Modeling; Mouse Strains; Mus; Mutate; Natural Immunity; Oral; Pathogenesis; Phagosomes; Predisposition; Publishing; Receptor Signaling; Research; Role; Route; Salmonella; Salmonella infections; Salmonella typhimurium; Site; Systemic infection; TLR4 gene; Testing; Time; Toll-Like Receptor 1; Toll-like receptors; Vacuole; Virulence; Virulent; base; cell type; divalent metal; foodborne; gene induction; in vivo; intraperitoneal; macrophage; oral infection; pathogen; public health relevance; receptor function

DESCRIPTION (provided by applicant): This application seeks to understand how the innate immune system influences the pathogenesis of Salmonella typhimurium. We are studying this issue by examining Salmonella virulence in mice and cells deficient in Toll- like receptors (TLRs). To unmask potentially critical host-pathogen interactions in this model, we have generated these TLR-deficient strains with a functional allele of Nramp-1, a divalent metal transporter that is mutated in many inbred mouse strains. Lack of functional Nramp-1 renders mice extremely susceptible to intracellular pathogens. Using these mouse strains we have made the surprising discovery that TLR- dependent phagosome acidification is required for induction of SPI-2 virulence genes. Thus, in macrophages lacking most or all TLR signaling, Salmonella is unable to create a replicative compartment. Surprisingly, this requirement for TLR signaling is only evident in cells with functional Nramp-1, suggesting that both TLRs and Nramp-1 manipulate the phagosomal environment. Salmonella is less virulent in mice lacking some, but not all, TLR signaling, consistent with an inability to replicate in macrophages. However, mice completely lacking TLR signaling are quite susceptible to Salmonella, suggesting that Salmonella is somehow able to cause disease in these animals without replicating in macrophages. The Aims of this grant focus on understanding how Nramp-1 and TLRs influence the niche where Salmonella replicates. In Aim 1, we will examine how Nramp-1 influences the phagosomal environment in the absence of TLR signaling. In Aim 2, we will examine how the level of TLR signaling can influence where Salmonella replicates in vivo. In Aim 3, we will exploit Salmonella's requirement for TLR signaling in mice with reduced TLR function. This requirement will be used to identify key cell types in which Salmonella must replicate while spreading systemically from intestinal sites.

描述（由申请人提供）：本申请试图了解先天免疫系统如何影响沙门氏菌伤寒的发病机理。我们通过检查小鼠的沙门氏菌毒力和细胞缺乏收费受体（TLR）来研究这个问题。为了揭示该模型中潜在的临界宿主 - 病原体相互作用，我们已经与NRAMP-1的功能性等位基因（一种二价金属转运蛋白，在许多近交小鼠菌株中突变。缺乏功能性NRAMP-1使小鼠非常容易受到细胞内病原体的影响。使用这些小鼠菌株，我们提出了一个令人惊讶的发现，即诱导SPI-2毒力基因需要依赖于TLR的吞噬体酸化。因此，在缺乏大多数或所有TLR信号传导的巨噬细胞中，沙门氏菌无法创建复制室。令人惊讶的是，这种对TLR信号传导的需求仅在具有功能性NRAMP-1的细胞中很明显，这表明TLRS和NRAMP-1都操纵了吞噬体环境。沙门氏菌在缺乏某些（但不是全部）TLR信号的小鼠中毒性较小，这与无法在巨噬细胞中复制一致。然而，完全缺乏TLR信号传导的小鼠非常容易受到沙门氏菌的影响，这表明沙门氏菌能够在某种程度上引起这些动物的疾病，而无需在巨噬细胞中复制。这项赠款的目的是理解NRAMP-1和TLR如何影响沙门氏菌复制的利基市场。在AIM 1中，我们将研究NRAMP-1在没有TLR信号传导的情况下如何影响吞噬体环境。在AIM 2中，我们将研究TLR信号的水平如何影响沙门氏菌在体内复制的位置。在AIM 3中，我们将利用 沙门氏菌对TLR功能降低的小鼠TLR信号的需求。该需求将用于识别沙门氏菌必须复制的关键细胞类型，同时从肠道部位进行系统地扩散。