Impact of inflammatory lipids on Yersinia pestis infection

炎性脂质对鼠疫耶尔森菌感染的影响

• 批准号: 10722648
• 负责人: Matthew B Lawrenz
• 金额: $ 72.35万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722648
• 关键词: Acute; Animal Model; Bacteria; Bacterial Infections; Biology; Cells; Chemotactic Factors; Data; Disease; Eicosanoids; Environment; Event; Family; Goals; Immune; Immune Evasion; Immune response; Infection; Infection Control; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune System; Kinetics; Leukocytes; Leukotriene B4; Lipids; Lipoxygenase; Lung; Macrophage; Mediating; Molecular; Mus; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Plague; Pneumonic Plague; Predisposition; Production; Proliferating; Prostaglandin-Endoperoxide Synthase; Proteins; Role; Signal Transduction; Site; System; Testing; Therapeutic Intervention; Time; Tissues; Type III Secretion System Pathway; Virulence; Virulence Factors; Yersinia pestis; chemokine; cytokine; defined contribution; host colonization; human disease; immunoregulation; improved; in vivo; innovation; insight; leukocyte mediator; lipid mediator; mast cell; member; mutant; neutrophil; novel; pathogen; recruit; response; tool

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.

抽象的 耶尔森氏念珠菌引起的急性人类疾病通常称为瘟疫。标志的表现 尽管有活跃的细菌复制，该疾病仍延迟炎症。 Y. Pestis通过 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 通过细菌三型分泌系统（T3S）直接注入宿主细胞的效应子。因为 建立这种非炎症环境是Y. Pestis殖民主持人的关键，了解如何了解 Y. Pestis调节感染早期宿主炎症反应将提供关键的见解 融入细菌的发病机理和改善治疗的潜在策略。脂质介质，例如 作为eicosanoid家族的成员，对于启动调节的信号事件的级联对于启动至关重要 炎。因此，促炎类花生酸的合成的破坏可以有效地扼杀快速 免疫反应。尽管它们在发炎中很重要，但脂质介质在 瘟疫以前尚未被调查。最近，我们发现了类花生酸合成的失调 在肺炎瘟疫期间，在促炎性脂质白细胞中的抑制作用突出显示 B4（LTB4）。此外，使用Y. Pestis突变体我们发现了一种新的机制来识别 T3SS由触发LTB4合成的中性粒细胞，通常受YOP效应子抑制。一起， 这些发现支持了概念上创新的假设，Y. Pestis积极操纵合成 脂质介质的破坏通常会募集循环白细胞的适当炎症级联 控制感染。在AIM 1中，我们将使用动物模型检验该假设，以定义 鼠疫期间对宿主反应的类固醇对LTB4合成的破坏有益于y。 瘟疫。在AIM 2中，我们将使用Y. Pestis作为定义负责T3SS-的分子机制的工具 中性粒细胞合成依赖性LTB4。因为炎症的脂质介质在 Y. Pestis免疫逃避的背景，这些研究的完成将极大地改变我们的概念 了解肺鼠疫期间的早期免疫事件。