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: 10296752
• 负责人: Matthew B Lawrenz
• 金额: $ 57.86万
• 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/10296752
• 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; Structure; System; Testing; Therapeutic; Time; Transition Elements; Virulence; Virulence Factors; Work; Yersinia pestis; Zinc; combat; design; efflux pump; fitness; human disease; improved; inhibitor/antagonist; innovation; mouse model; mutant; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pathogen; pathogenic bacteria; permease; 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