Neutrophil Extracellular Traps and Haemophilus ducreyi

中性粒细胞胞外陷阱和杜克雷嗜血杆菌

• 批准号: 8311612
• 负责人: MARGARET E BAUER
• 金额: $ 7.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311612
• 关键词: Affect; Alternative Therapies; Antibiotic Resistance; Area; Bacteria; Bacterial Infections; Cells; Chromatin Fiber; Cytoplasmic Granules; DNA; Data; Deoxyribonucleases; Disease; Environment; Fiber; Focal Infection; Foundations; Genital system; Goals; HIV; Hemophilus ducreyi; Human; Human Activities; Immune; Immune response; Infection; Left; Life; Mediating; Natural Immunity; Organism; Pathogenesis; Peptide Hydrolases; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pilot Projects; Predisposition; Process; Production; Reactive Oxygen Species; Relative (related person); Reporting; Research; Resistance; Role; Sexually Transmitted Diseases; Skin; Specimen; Structure; System; Testing; Therapeutic Agents; Tissues; Ulcer; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; bactericide; base; capsule; combat; extracellular; human tissue; improved; in vitro activity; in vivo; killings; neutrophil; novel; pathogen; pressure; resistance mechanism; response; transmission process

DESCRIPTION (provided by applicant): Haemophilus ducreyi is the causative agent of chancroid, a sexually transmitted genital ulcer disease that facilitates transmission and acquisition of human immunodeficiency virus (HIV) and thus contributes to the spread of HIV in areas with endemic chancroid. The increase in antibiotic resistance observed among H. ducreyi strains has greatly narrowed drug choices for treatment of chancroid; thus, alternative therapies against H. ducreyi are needed. During human infection, H. ducreyi resides extracellularly in an environment surrounded by professional phagocytes, including neutrophils, a key component of the innate immune response. When unable to phagocytose extracellular pathogens, neutrophils undergo the newly described process of extruding chromatin fibers that are decorated with antimicrobial components from the neutrophil's granules. These DNA-based structures, termed neutrophil extracellular traps (NETs), can ensnare bacteria that then are killed by the antimicrobial components. Very little is known about how bacterial pathogens overcome NET-mediated killing. Although the pathogenesis of H. ducreyi suggests that NET formation likely occurs during H. ducreyi infection, the interactions of this significant human pathogen with NETs has not been studied. The long-term goal of this project is to understand mechanisms of NET resistance in H. ducreyi so that novel antimicrobial agents can be developed that target these NET resistance mechanisms. We hypothesize that NET formation occurs in response to H. ducreyi but that the pathogen has mechanisms to survive NET formation in vivo. Our preliminary data suggest that H. ducreyi may survive NETs by novel mechanisms. The Aims of this application are to establish the presence of NETs during H. ducreyi infection, localize H. ducreyi relative to NETs in vivo, and define the susceptibility of H. ducreyi to NET-mediated killing. These studies will establish a system for defining novel mechanisms by which pathogens resist NET-mediated killing. Such mechanisms will likely serve as useful targets of novel therapeutic agents to combat chancroid and possibly other extracellular bacterial infections.

描述（由申请人提供）：杜克雷嗜血杆菌是软下疳的病原体，软下疳是一种性传播的生殖器溃疡病，可促进人类免疫缺陷病毒（HIV）的传播和获得，从而促进艾滋病毒在软下疳流行地区的传播。杜克雷螺杆菌菌株中观察到的抗生素耐药性的增加大大缩小了治疗软下疳的药物选择范围；因此，需要针对杜克雷螺杆菌的替代疗法。在人类感染期间，杜克雷螺杆菌存在于细胞外的环境中，周围有专业的吞噬细胞，包括中性粒细胞，这是先天免疫反应的关键组成部分。当无法吞噬细胞外病原体时，中性粒细胞会经历新描述的挤出染色质纤维的过程，这些纤维装饰有中性粒细胞颗粒中的抗菌成分。这些基于 DNA 的结构被称为中性粒细胞胞外陷阱 (NET)，可以诱捕细菌，然后细菌被抗菌成分杀死。关于细菌病原体如何克服 NET 介导的杀伤作用，人们知之甚少。尽管杜克雷嗜血杆菌的发病机制表明，在杜克雷嗜血杆菌感染期间可能发生 NET 的形成，但这种重要的人类病原体与 NET 的相互作用尚未得到研究。该项目的长期目标是了解杜克雷螺杆菌的 NET 耐药机制，以便开发针对这些 NET 耐药机制的新型抗菌药物。我们假设 NET 的形成是对杜克雷螺杆菌的反应，但病原体具有在体内存活 NET 形成的机制。我们的初步数据表明，H. ducreyi 可能通过新颖的机制在 NET 中存活。本申请的目的是确定杜克雷嗜血杆菌感染期间 NET 的存在，相对于体内 NET 定位杜克雷嗜血杆菌，并确定杜克雷嗜血杆菌对 NET 介导的杀伤的敏感性。这些研究将建立一个系统来定义病原体抵抗 NET 介导的杀伤的新机制。这种机制可能会成为对抗软下疳和其他可能的细胞外细菌感染的新型治疗剂的有用靶点。