Iron independent role for yersiniabactin in Yersinia pestis

耶尔森菌素在鼠疫耶尔森氏菌中的铁独立作用

• 批准号: 10418805
• 负责人: Matthew B Lawrenz
• 金额: $ 54.62万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-04 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418805
• 关键词: 3-Dimensional; Affinity; Attenuated; Bacteria; Binding; Bubonic Plague; Cells; Characteristics; Chemicals; Crystallography; Data; Defect; Development; Drug Targeting; Foundations; Goals; Gram-Negative Bacteria; Hemochromatosis; Human; Immune response; In Vitro; Infection; Iron; Kinetics; Lead; Leukocyte L1 Antigen Complex; Leukocytes; Mammals; Mediating; Membrane; Metals; Modeling; Molecular; Mus; Mutagenesis; Nutritional Immunity; Plague; Pneumonic Plague; Predisposition; Prevention; Proteins; Pump; Research Personnel; Role; Siderophores; Solid; Specificity; System; Testing; Therapeutic; Time; Transition Elements; Virulence; Virulence Factors; Work; Yersinia pestis; Zinc; combat; efflux pump; fitness; human disease; improved; inhibitor; innovation; mouse model; mutant; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic bacteria; permease; rational design; receptor; response; therapeutic candidate; therapeutic target; transposon sequencing; yersiniabactin

SUMMARY Transitional metals (e.g., Fe, Zn, Mn) are required by bacteria in order to grow. As such, mammals have a variety of mechanisms to sequester these metals during infection, effectively limiting their availability for use by bacteria (referred to as nutritional immunity). Yersinia pestis, which causes the human disease plague, needed to evolve high-affinity metal acquisition mechanisms to overcome nutritional immunity and colonize its hosts. Because these mechanisms are key to Y. pestis virulence, they represent potential therapeutic targets for the treatment or prevention of plague. Therefore, our long term goals are to identify the mechanisms used by Y. pestis to evade host nutritional immunity and define their roles in virulence. Recently, we have made the exciting discovery that yersiniabactin (Ybt), a siderophore essential for Y. pestis iron (Fe) acquisition, is also able to bind to zinc (Zn), and contributes to Zn acquisition in vitro. Furthermore, using a hemochromatosis mouse model that is defective in Fe-mediated nutritional immunity, we demonstrated for the first time that Ybt contributes to virulence in an Fe-independent manner. Using a Y. pestis mutant defective in Zn acquisition, was also showed that the host protein calprotectin, which is a key component to Zn-mediated nutritional immunity, is a barrier to Y. pestis infection, and Ybt contributes to overcoming this barrier in both pneumonic and bubonic plague. Together, these data are our premise for the conceptually innovative hypothesis that Ybt not only contributes to virulence through Fe acquisition, but also contributes to Zn acquisition, which aids in overcoming calprotectin mediated nutritional immunity. In this proposal, we will build on these exciting discoveries. In Aim 1, we will define the mechanisms that govern metal selectivity of Ybt and the re-acquisition of Ybt-Zn by the bacterium. In Aim 2, we will define the Ybt secretion mechanisms used by Y. pestis and determine the therapeutic potential of inhibiting these secretion systems during plague. Finally, in Aim 3, we will define the role of host calprotectin during plague and the contribution of Ybt to the ability of Y. pestis in overcoming calprotectin mediated Zn sequestration. Importantly, Ybt is a conserved virulence factor in many Gram-negative bacteria. Therefore, the data generated from these studies has the potential to provide us with a broader understanding of the role of Ybt in the virulence of multiple pathogens. Ultimately, these data will provide a foundation for the rational design of new therapeutic approaches targeting these mechanisms to combat Y. pestis infection.

概括 为了生长，细菌需要过渡金属（例如Fe，Zn，MN）。因此，哺乳动物有一个 在感染过程中隔离这些金属的各种机制，有效地限制了它们的使用量 细菌（称为营养免疫）。引起人类疾病的耶尔森氏念珠菌需要 进化高亲和力的金属采集机制来克服营养免疫并定居其宿主。 由于这些机制是耶和华毒力的关键，因此它们代表了潜在的治疗靶标的 治疗或预防鼠疫。因此，我们的长期目标是确定Y使用的机制。 审查宿主营养免疫并定义其在毒力中的作用。最近，我们使令人兴奋的 发现Yersiniabactin（YBT）是Y. Pestis Iron（Fe）获得必不可少的铁载体，也能够结合 到锌（Zn），并在体外有助于Zn获取。此外，使用血色素沉着小鼠模型 在Fe介导的营养免疫力中有缺陷，我们首次证明了YBT有助于 以Fe独立的方式毒力。在Zn采集中使用Y. pestis突变体有缺陷，也显示了 宿主蛋白钙卫蛋白是Zn介导的营养免疫的关键成分，是障碍 Y. Pestis感染，YBT有助于克服肺炎和Bubonic瘟疫中的这一障碍。 这些数据在一起是我们在概念上创新假设的前提，即YBT不仅有助于 通过获取FE的毒力，但也有助于Zn获取，这有助于克服钙蛋白钙蛋白酶素 介导的营养免疫。在此提案中，我们将基于这些令人兴奋的发现。在AIM 1中，我们将定义 通过细菌对YBT的金属选择性的机制以及YBT-ZN的重新收到的机制。在AIM 2中， 我们将定义Y. Pestis使用的YBT分泌机制，并确定 在鼠疫期间抑制这些分泌系统。最后，在AIM 3中，我们将定义宿主calprotectin的作用 在瘟疫期间和YBT对YBT的贡献在克服钙染色蛋白介导的锌中的能力 隔离。重要的是，YBT是许多革兰氏阴性细菌中保守的毒力因子。因此， 这些研究产生的数据有可能使我们对YBT的作用有更广泛的了解 在多种病原体的毒力中。最终，这些数据将为合理设计提供基础 针对这些机制来对抗病虫感染的新治疗方法。