Mechanisms of persistent Salmonella infection

持续性沙门氏菌感染的机制

• 批准号: 10510554
• 负责人: Denise M Monack
• 金额: $ 45.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10510554
• 关键词: Anti-Inflammatory Agents; Bacteria; Bacterial Infections; Biochemical; Carrier State; Cells; Chronic; Clinical; Critical Pathways; Data; Disease Progression; Disease Reservoirs; Gene Expression Profiling; Genetic; Goals; Granuloma; Health; Human; Immune; Immune response; Immunity; Immunologics; Infection; Inflammatory; Inflammatory Response; Knowledge; MAPK8 gene; Macrophage; Mediating; Metabolic; Molecular; Monitor; Morbidity - disease rate; Morphology; Mus; NF-kappa B; Nature; Oral; Pathogenesis; Pathway interactions; Phenotype; Preventive; Publishing; Regulation; Research; Risk; Role; Route; STAT3 gene; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Signal Pathway; Signal Transduction; Sorting; System; Systemic infection; TLR4 gene; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Type III Secretion System Pathway; Virulence Factors; Visualization; chronic infection; disease transmission; enteric pathogen; immunopathology; innovation; insight; man; microbial; mortality; novel marker; pathogen; persistent bacterial infection; pharmacologic; preventive intervention; transcription factor; transcriptomics; transmission process

ABSTRACT Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically within granulomas for long periods of time. Persistently infected hosts are often asymptomatic and transmit disease to naïve hosts, thereby serving as a critical reservoir for disease. From the bacterial perspective, persistent infection is essential for microbial survival in nature. However, very little is known about the molecular mechanisms involved in persistent Salmonella infections and transmission between mammalian hosts. Increased knowledge of the molecular mechanisms of Salmonella persistence may lead to the ability to eradicate the Salmonella carrier state pharmacologically. Our long-term goal is to understand how Salmonella persists within tissues of mammalian hosts for preventive and therapeutic purposes. The objective of this proposal, which is our next step in pursuit of this goal, is to identify host pathways involved in granuloma dynamics and to determine how Salmonella manipulates host cells for long-term survival. The premise that will be tested in this application is that Salmonella injects virulence factors into granuloma macrophages that both promote an anti-inflammatory state and block specific proinflammatory responses in order to persist in mammalian hosts. We propose to study the molecular mechanisms of persistent Salmonella infections in granulomas of mammalian hosts. Aim 1 will characterize the cellular organization and molecular regulation of granulomas during persistent Salmonella mouse infection, with a particular focus on visualization and analysis of gene expression of granuloma macrophages in tissue sections by spatial transcriptomics. In Aim 2, we will identify mechanisms of Salmonella-dependent manipulation of granuloma macrophages. Aim 3 will characterize the role of the Type 6 secretion system during persistent Salmonella infection. The proposed research is innovative because we investigate the spatial transcriptomics of granuloma macrophages, a heretofore- unexamined pathogen niche. Insight into host-pathogen interactions during persistent infection of a mammalian host is impactful as novel biomarkers and treatments of asymptomatic carriers are needed for eradication of this disease reservoir.

摘要 肠道沙门氏菌宿主适应株可引起全身性感染，并具有持续全身性的能力 长时间在肉芽肿内。持续感染的宿主通常没有症状，并通过 疾病传染给幼稚的宿主，从而成为疾病的关键蓄水池。从细菌的角度来看， 持续感染对微生物在自然界中的生存是必不可少的。然而，人们对这种分子知之甚少。 持续沙门氏菌感染和哺乳动物宿主之间传播的机制。 对沙门氏菌持久性分子机制的了解增加可能会导致根除 沙门氏菌携带者的药理状态。我们的长期目标是了解沙门氏菌是如何 持续存在于哺乳动物宿主的组织内，用于预防和治疗目的。这样做的目的是 建议，这是我们追求这一目标的下一步，是确定肉芽肿的宿主途径 目的是研究沙门氏菌如何操纵宿主细胞以获得长期生存。前提是将 在这一应用中测试的是沙门氏菌将毒力因子注入肉芽肿巨噬细胞， 促进抗炎状态并阻断特定的促炎反应，以便持续 哺乳动物的宿主。我们建议研究沙门氏菌持续感染的分子机制。 哺乳动物宿主肉芽肿。目标1将描述细胞组织和分子调控 沙门氏菌持续感染小鼠期间的肉芽肿，特别关注可视化和分析 用空间转录组学方法研究肉芽肿巨噬细胞在组织切片中的基因表达。在目标2中，我们将 确定沙门氏菌依赖的对肉芽肿巨噬细胞的操纵机制。《目标3》将描述 6型分泌系统在沙门氏菌持续感染中的作用。拟议的研究是 创新是因为我们研究了肉芽肿巨噬细胞的空间转录，在此之前- 未经检验的病原体生态位。哺乳动物持续感染期间宿主与病原体相互作用的洞察 宿主是有影响的，因为新的生物标志物和无症状携带者的治疗需要根除 病源。