Impact of inflammatory lipids on Yersinia pestis infection

摘要 鼠疫耶尔森氏菌引起的急性人类疾病通常被称为鼠疫。这是 尽管细菌复制活跃，但这种疾病是延迟性炎症。Y.鼠疫通过以下方式调节炎症： 通过一组称为Yop的蛋白质的作用，积极抑制促炎细胞因子的表达 通过细菌3型分泌系统（T3SS）直接注入宿主细胞的效应物。因为 这种非炎症环境的建立是Y.鼠疫菌在宿主中定居， Y.鼠疫在感染早期调节宿主的炎症反应， 研究细菌的发病机制和改善治疗的潜在策略。脂质介质，如 作为类二十烷酸家族的成员，对于启动级联的信号传导事件是必需的， 炎症因此，破坏促炎性类二十烷酸的合成可以有效地抑制快速炎症反应。 免疫反应尽管它们在引发炎症中的重要性，脂质介质在炎症背景下的作用仍有待进一步研究。 鼠疫以前没有调查过。最近，我们发现类花生酸合成失调， 肺鼠疫期间，促炎脂质白三烯合成的抑制凸显了这一点 B4（LTB4）。此外，使用Y.我们发现了一种新的机制， T3SS由中性粒细胞触发LTB4合成，其通常由Yop效应子抑制。在一起， 这些发现支持了一个概念上创新的假设，即Y.鼠疫主动操纵合成 脂质介质破坏适当的炎症级联反应，通常会招募循环白细胞 来控制感染在目标1中，我们将使用动物模型来测试这一假设，以确定 类花生酸对鼠疫期间宿主反应的影响，并确定LTB4合成的破坏如何使Y. 鼠疫在目标2中，我们将使用Y。鼠疫作为一种工具，以确定负责T3SS的分子机制， 中性粒细胞依赖性LTB 4合成。由于炎症的脂质介质在炎症过程中被忽视， Y的背景。鼠疫免疫逃避，完成这些研究将大大改变我们的概念 了解肺鼠疫早期免疫事件。

ABSTRACT Yersinia pestis causes the acute human disease commonly referred to as plague. A hallmark manifestation of this disease is delayed inflammation despite active bacterial replication. Y. pestis modulates inflammation by actively inhibiting the expression of pro-inflammatory cytokines via the action of a group of proteins called Yop effectors that are directly injected into host cells by a bacterial type three secretion system (T3SS). Because establishment of this non-inflammatory environment is key for Y. pestis to colonize the host, understanding how Y. pestis modulates the host inflammatory response during early stages of infection will provide crucial insights into both the pathogenesis of the bacterium and potential strategies to improve therapy. Lipid mediators, such as members of the eicosanoid family, are essential to initiate the cascade of signaling events that regulates inflammation. Therefore, disruption of the synthesis of pro-inflammatory eicosanoids can effectively stifle a rapid immune response. Despite their importance in initiating inflammation, the role of lipid mediators in the context of plague has not been previously investigated. Recently, we discovered a dysregulation in eicosanoid synthesis during pneumonic plague, highlighted by the inhibition in the synthesis of the pro-inflammatory lipid leukotriene B4 (LTB4). Furthermore, using Y. pestis mutants we uncovered a novel mechanism for the recognition of the T3SS by neutrophils that triggers LTB4 synthesis, which is normally inhibited by the Yop effectors. Together, these discoveries support a conceptually innovative hypothesis that Y. pestis actively manipulates the synthesis of lipid mediators to disrupt the proper inflammatory cascade that would normally recruit circulating leukocytes to control infection. In Aim 1, we will test this hypothesis using animal models to define the contribution of eicosanoids to the host response during plague and determine how disruption of LTB4 synthesis benefits Y. pestis. In Aim 2, we will use Y. pestis as a tool to define the molecular mechanisms responsible for T3SS- dependent LTB4 synthesis by neutrophils. Because lipid mediators of inflammation have been overlooked in the context of Y. pestis immune evasion, completion of these studies will significantly transform our conceptual understanding of the early immune events during pneumonic plague.