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

鼠疫已造成数百万人死亡，客观上令人担忧的是，鼠疫耶尔森氏菌可能被用来 威胁公众健康。Y.鼠疫菌是从Y.假结核两者都是亲淋巴细胞的， 惊人的双相疾病：最初的细菌复制没有炎症让位于深刻的 炎症、组织破坏和临床疾病。复制在早期没有有效的宿主响应 感染也是伯克霍尔德氏菌属和弗朗西斯氏菌属特征。只有早期干预才能挽救感染者 患者和更好地了解感染的初始阶段，以及先天反应如何延迟， 将改善诊断和治疗的方法。细菌属性和宿主反应在早期 淋巴结感染仍是一个未被研究课题。耶尔森氏菌表面和分泌的蛋白质，这可能是 对早期感染至关重要，也是亚单位疫苗或诊断标记物的候选者， 使用蛋白质组学、生物信息学和表达阵列研究鉴定。调查将集中在细菌 在已知调节表面变化的基因中具有确定突变的菌株， 对有效模仿宿主环境的环境刺激作出响应。细菌突变体缺乏 这些蛋白质在宿主淋巴结中的生长将使用不 由于质粒编码分泌系统的无数作用而变得复杂。主机对限制的贡献 淋巴结中的细菌生长，以及耶尔森氏菌感染引发的淋巴增殖， 研究以了解哪些淋巴细胞正在增殖以及它们是否被激活， 有助于限制感染的细胞因子。细菌感染需要精确调节炎症 复制发生在体内，因此，细胞活化和生产的贡献 细胞因子将在宿主对以下应答的背景下进行评价：i）定殖于淋巴结的细菌菌株， 和ii）不能定殖的有缺陷的高度炎性菌株。该项目将提供更大的 了解对感染的先天免疫反应，并为设计最佳的 诊断和治疗策略，有利于受感染宿主的质量结果。

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.