Mechanisms of persistent Salmonella infection

持续性沙门氏菌感染的机制

• 批准号: 10756889
• 负责人: Denise M Monack
• 金额: $ 9.66万
• 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/10756889
• 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 肠道沙门氏菌的宿主适应菌株引起全身感染，并具有持续全身感染的能力 在肉芽肿中长时间存在。持续感染的宿主通常无症状， 疾病传播给幼稚宿主，从而成为疾病的关键储存库。从细菌的角度来看， 持续感染对于微生物在自然界中的生存是必不可少的。然而，人们对这种分子结构知之甚少。 沙门氏菌持续感染和哺乳动物宿主之间传播的机制。 增加对沙门氏菌持续存在的分子机制的了解可能会导致根除沙门氏菌的能力。 沙门氏菌携带者州我们的长期目标是了解沙门氏菌 持续存在于哺乳动物宿主的组织中，用于预防和治疗目的。的目的 我们的下一步目标是确定肉芽肿的宿主通路 动力学，并确定沙门氏菌如何操纵宿主细胞的长期生存。前提是， 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，以持续 哺乳动物宿主我们建议研究持续性沙门氏菌感染的分子机制， 哺乳动物宿主的肉芽肿。目的1将表征细胞组织和分子调控， 持续性沙门氏菌感染小鼠期间的肉芽肿，特别关注可视化和分析 组织切片中肉芽肿巨噬细胞基因表达的空间转录组学。在目标2中，我们将 沙门氏菌依赖性肉芽肿巨噬细胞操纵机制的鉴定。目标3将描述 6型分泌系统在持续性沙门氏菌感染中的作用。拟议的研究是 创新，因为我们研究了肉芽肿巨噬细胞的空间转录组学，迄今为止， 未经检验的病原体生态位哺乳动物持续感染过程中宿主-病原体相互作用的研究 宿主是有影响的，因为需要新的生物标志物和无症状携带者的治疗来根除这种疾病。 病源