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: 10789295
• 负责人: Matthew B Lawrenz
• 金额: $ 1.58万
• 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/10789295
• 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; 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.

总结 过渡金属（例如，Fe、Zn、Mn）是细菌生长所必需的。因此，哺乳动物具有 在感染期间隔离这些金属的各种机制，有效地限制了它们的可用性， 细菌（称为营养免疫）。导致人类疾病鼠疫的耶尔森氏菌需要 进化出高亲和力的金属获取机制，以克服营养免疫并在宿主中定居。 因为这些机制是Y.鼠疫毒力，他们代表了潜在的治疗目标， 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。 鼠疫逃避宿主的营养免疫，并确定其在毒力中的作用。最近，我们制作了令人兴奋的 发现耶尔森氏杆菌素（Ybt）是Y.鼠疫铁（Fe）的收购，也能够结合 锌（Zn），并有助于锌收购在体外。此外，使用血色病小鼠模型， 铁介导的营养免疫缺陷，我们首次证明，Ybt有助于 毒力不依赖于铁。使用Y。鼠疫菌锌吸收缺陷突变体 宿主蛋白钙卫蛋白是锌介导的营养性免疫的关键成分，是 Y. Ybt有助于克服肺鼠疫和淋巴腺鼠疫的这一障碍。 总之，这些数据是我们在概念上创新假设的前提，即Ybt不仅有助于 毒力通过铁的获取，但也有助于锌的获取，这有助于克服钙卫蛋白 介导的营养免疫。在本提案中，我们将以这些令人兴奋的发现为基础。在目标1中，我们定义 控制Ybt的金属选择性和细菌重新获得Ybt-Zn的机制。在目标2中， 我们将定义Y.鼠疫和确定的治疗潜力 在瘟疫期间抑制这些分泌系统。最后，在目标3中，我们将定义宿主钙卫蛋白的作用， 以及Ybt对鼠疫菌鼠疫能力的贡献。鼠疫菌对钙卫蛋白介导的锌的耐受作用 隔离重要的是，Ybt是许多革兰氏阴性细菌中的保守毒力因子。因此 从这些研究中获得的数据有可能使我们对Ybt的作用有更广泛的了解 多种病原体的毒力。最终，这些数据将为合理设计提供基础 新的治疗方法针对这些机制，以打击Y。鼠疫感染