Host and pathogen-associated mechanisms of Yersinia survival in lumph nodes

耶尔森菌在肿块淋巴结中存活的宿主和病原体相关机制

• 批准号: 7675881
• 负责人: BRAD T COOKSON
• 金额: $ 30.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675881
• 关键词: Animal Model; Apoptosis; Attenuated; B-Lymphocytes; Bacteria; Bacterial Genes; Bacterial Infections; Bioinformatics; Bromodeoxyuridine; Burkholderia; Caspase-1; Categories; Cell Death; Cells; Centers of Research Excellence; Characteristics; Clinical; Cultured Cells; Data; Detection; Diagnosis; Diagnostic; Disease; Early treatment; Elements; Emerging Communicable Diseases; Environment; Event; Failure; Francisella; Genes; Growth; Hour; Human; Hyperplasia; Immune; Immune response; Immunity; Immunophenotyping; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knockout Mice; Label; Laboratories; Libraries; Life; Lung; Lymphadenitis; Lymphocyte; Lymphoid; Macrophage Activation; Mediating; Modification; Mus; Mutagenesis; Mutation; Organism; Outcome; Pasteurella pseudotuberculosis; Pathogenesis; Patients; Pattern recognition receptor; Plague; Plasmids; Play; Predisposition; Process; Production; Proliferating; Proteins; Proteomics; Public Health; Receptor Signaling; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Sepsis; Signal Pathway; Signal Transduction; Staging; Staining method; Stains; Stimulus; Subunit Vaccines; Surface; System; Systemic infection; T-Lymphocyte; TLR2 gene; TLR4 gene; Temperature; Testing; Therapeutic; Tissues; Transgenic Mice; Type III Secretion System Pathway; Virulence; Work; Yersinia; Yersinia infections; Yersinia pestis; antimicrobial; biodefense; cytokine; design; disease diagnosis; experience; extracellular; genetic regulatory protein; improved; in vivo; infected B cell; insight; interdisciplinary approach; killings; lymph nodes; lymphocyte proliferation; lymphoid hyperplasia; macrophage; mutant; pathogen; research study; response; success; treatment strategy

Plague has killed millions of humans, providing objective concern that Yersinia pestis could be used to threaten public health. Y. pestis evolved from Y. pseudotuberculosis. Both are lymphotropic and cause strikingly bi-phasic illnesses: initial bacterial replication without inflammation gives way to profound inflammation, tissue destruction, and clinical disease. Replication without effective host responses in early infection is also characteristic of Burkholderia and Francisella. Only early intervention can save infected patients and a better understanding of the initial stages of infection, and how innate responses are delayed, will improve approaches to diagnosis and treatment. Bacterial attributes and host responses during early lymph node infection remain largely unstudied. Yersinia surface and secreted proteins, which are likely to be critical for early infection and are also candidates for subunit vaccines or diagnostic markers, will be identified using proteomics, bioinformatics and expression array studies. Investigation will focus on bacterial strains with defined mutations in genes known to regulate surface changes and comparing bacteria responding to environmental stimuli that effectively mimic the host environment. Bacterial mutants lacking these proteins will be assessed for growth in host lymph nodes using an experimental system that is not complicated by the myriad effects of the plasmid-encoded secretion system. Host contributions to limiting bacterial growth in the lymph node, and the lymphoid proliferation triggered by Yersinia infections, will be investigated to understand which lymphocytes are proliferating and whether or not they are activated and contributing cytokines to help limit infection. Precise modulation of inflammation is required for bacterial replication to occur in vivo, and therefore the contributions of both cellular activation and the production of cytokines will be evaluated in the context of host responses to: i) bacterial strains that colonize lymph nodes, and ii) defective hyper-inflammatory strains that fail to colonize. This project will provide a greater understanding of innate immune responses to infection and provide relevant data for designing optimal diagnostic and treatment strategies that favor quality outcomes for the infected host.

鼠疫已导致数百万人死亡，客观上令人担忧鼠疫杆菌可能被用来 威胁公众健康。鼠疫杆菌是由假结核杆菌进化而来的。两者都是嗜淋巴的和致病的 惊人的双相疾病：最初的细菌复制没有炎症，取而代之的是 炎症、组织破坏和临床疾病。早期没有有效主机响应的复制 感染也是伯克霍尔德氏菌和方济各氏菌的特征。只有早期干预才能挽救感染者 并更好地了解感染的初始阶段，以及先天反应是如何延迟的， 将改进诊断和治疗方法。早期细菌属性和寄主反应 淋巴感染在很大程度上仍未得到研究。耶尔森氏菌表面和分泌的蛋白质，很可能是 对早期感染至关重要，也是亚单位疫苗或诊断标记的候选者将是 使用蛋白质组学、生物信息学和表达阵列研究进行鉴定。调查将集中在细菌上 具有已知的调节表面变化的基因明确突变的菌株和比较细菌 对有效模拟宿主环境的环境刺激作出反应。细菌突变体缺失 这些蛋白质将使用一种实验系统进行评估，以确定其在宿主淋巴结中的生长情况 被质粒编码的分泌系统的无数效应所复杂化。主机对限制的贡献 细菌在淋巴结中的生长，以及耶尔森菌感染引发的淋巴组织增殖，将是 调查以了解哪些淋巴细胞正在增殖以及它们是否被激活和 贡献细胞因子来帮助限制感染。细菌需要对炎症进行精确的调节 复制发生在体内，因此细胞激活和产生 细胞因子将在宿主对以下方面的反应的背景下进行评估：i)定植于淋巴结的细菌菌株， 以及ii)未能定植的有缺陷的高炎性菌株。该项目将提供更大的 了解对感染的先天免疫反应，并为优化设计提供相关数据 有利于感染宿主获得高质量结果的诊断和治疗策略。