Host recognition by pathogenic yersiniae

致病性耶尔森氏菌的宿主识别

• 批准号: 8386532
• 负责人: Francesca M Marassi
• 金额: $ 48.8万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386532
• 关键词: Adhesions; Affinity; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Adhesion; Bacterial Translocation; Base Sequence; Binding; Biological; Biological Assay; Cells; Classification; Complement; Data; Development; Engineering; Environment; Event; Fibronectins; Glare; Goals; Human; Immune system; Liposomes; Magic; Maps; Mediating; Membrane Proteins; Methods; Micelles; Molecular; Molecular Structure; Mutagenesis; Organism; Pathogenicity; Phagocytosis; Phospholipids; Physiological; Plague; Proteins; Publishing; Recombinants; Research Activity; Resistance; Role; Sampling; Series; Signal Transduction; Solutions; Structure; Tertiary Protein Structure; TimeLine; Vaccines; Virulence Factors; Vitronectin; Work; Yersinia; Yersinia pestis; aerosolized; base; biothreat; design; extracellular; human mortality; in vitro Assay; mutant; new therapeutic target; polypeptide; protein protein interaction; solid state nuclear magnetic resonance; therapeutic development; three dimensional structure; weapons

DESCRIPTION (provided by applicant): Yersinia pestis, the causative agent of plague, is a highly pathogenic organism that spreads rapidly and causes extremely high human mortality. Although it is sensitive to a restricted panel of antibiotics, its extraordinary pathogenicity, the potential weaponization of aerosolized bacteria with bio-engineered antibiotic resistance, and the lack of an effective vaccine or therapy are major concerns, contributing to its classification as a Tier 1 Biothreat Agent. The outer membrane protein Ail is a Y. pestis virulence factor and a prime candidate for therapeutic development due to its two principal activities: (i) mediating the adhesion of Y. pestis bacteria to host cells, and (ii) providing resistance to human complement. This project focuses on understanding its adhesion activity as a step towards its development as a novel therapeutic target. The working hypothesis is that Ail binds one or more host proteins, triggering host intracellular signaling cascades and the translocation of bacterial factors into the host cell that block phagocytosis and enable bacteria to survive extracellularly. Adhesion is the first key step in this series of events; however, how does Ail mediate bacterial adhesion to human cells? Molecular information is lacking. The specific aims of this project are designed to fill this glaring gap by obtaining functional and structural information about the adhesion activity of Ail and the interactions with its human host partners. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to understand how Yersinia pestis, the causative agent of plague, attaches to human host cells and evades the human immune system. The potential use of plague as a biological weapon is of major concern and our studies will provide important information for therapeutic developments.

描述（由申请人提供）：鼠疫耶尔森氏菌是鼠疫的病原体，是一种高致病性生物，传播迅速，导致极高的人类死亡率。尽管它对有限的一组抗生素敏感，但其非凡的致病性， 具有生物工程抗生素耐药性的雾化细菌的潜在武器化，以及缺乏有效的疫苗或疗法是主要问题，导致其被归类为一级生物威胁制剂。外膜蛋白Ail是鼠疫耶尔森氏菌毒力因子，并且由于其两个主要活性而成为治疗开发的主要候选者：(i)介导鼠疫耶尔森氏菌与宿主细胞的粘附，以及(ii)提供对人类补体的抗性。该项目的重点是了解其粘附活性，作为其发展为新型治疗靶点的一步。工作假设是Ail结合一种或多种宿主蛋白​​，触发宿主细胞内信号级联和细菌因子易位到宿主细胞中，从而阻止吞噬作用并使细菌能够在细胞外生存。粘附是这一系列事件的第一个关键步骤；然而，Ail是如何介导细菌粘附到人体细胞上的呢？缺乏分子信息。该项目的具体目标是通过获取有关 Ail 粘附活性及其与人类宿主伙伴相互作用的功能和结构信息来填补这一明显的空白。 公共卫生相关性：该项目的总体目标是了解鼠疫病原体鼠疫耶尔森氏菌如何附着在人类宿主细胞上并逃避人类免疫系统。鼠疫作为生物武器的潜在用途是人们主要关注的问题，我们的研究将为治疗发展提供重要信息。