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(申请人提供)：本申请旨在了解先天免疫系统如何影响鼠伤寒沙门氏菌的发病机制。我们正在通过检测沙门氏菌在小鼠和Toll样受体(TLRs)缺陷细胞中的毒力来研究这个问题。为了揭示这个模型中潜在的关键宿主-病原体相互作用，我们产生了这些TLR缺陷菌株，其功能等位基因为Nramp-1，一种二价金属转运蛋白，在许多近交系小鼠中发生突变。缺乏功能的Nramp-1使小鼠非常容易受到细胞内病原体的影响。使用这些小鼠品系，我们有了令人惊讶的发现，依赖TLR的吞噬小体酸化是诱导SPI-2毒力基因所必需的。因此，在缺乏大部分或全部TLR信号的巨噬细胞中，沙门氏菌不能产生复制间隔。令人惊讶的是，对TLR信号的这种要求只在具有功能的Nramp-1的细胞中明显，这表明TLRs和Nramp-1都操纵吞噬体环境。沙门氏菌在缺乏部分但不是全部TLR信号的小鼠中毒力较低，这与无法在巨噬细胞中复制一致。然而，完全缺乏TLR信号的小鼠对沙门氏菌非常敏感，这表明沙门氏菌以某种方式能够在这些动物身上引起疾病，而不会在巨噬细胞中复制。这笔赠款的目的是了解Nramp-1和TLRs如何影响沙门氏菌复制的利基。在目标1中，我们将研究在缺乏TLR信号的情况下，Nramp-1如何影响吞噬环境。在目标2中，我们将研究TLR信号水平如何影响沙门氏菌在体内复制的位置。在目标3中，我们将利用 沙门氏菌对TLR功能低下小鼠TLR信号的需求。这一要求将用于确定沙门氏菌在从肠道部位系统性传播时必须在其中复制的关键细胞类型。