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: 8094089
• 负责人: MARGARET E BAUER
• 金额: $ 7.75万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094089
• 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. PUBLIC HEALTH RELEVANCE: Haemophilus ducreyi, which causes chancroid, is an important pathogen because of its ability to facilitate HIV transmission and its strong correlation with the spread of HIV in areas with endemic chancroid. The work in this application will define how H. ducreyi interacts with human neutrophils to survive a major mechanism neutrophils use to kill pathogens extracellularly. Understanding how H. ducreyi overcomes neutrophil attack will provide needed information to develop improved therapies to combat H. ducreyi and other extracellular pathogens of humans.

描述(申请人提供)：杜雷氏嗜血杆菌是下巴的病原体，这是一种性传播的生殖器溃疡疾病，有助于人类免疫缺陷病毒(HIV)的传播和获得，从而导致艾滋病毒在地方性下巴流行地区的传播。杜氏嗜血杆菌菌株对抗生素耐药性的增加极大地缩小了治疗软骨病的药物选择范围；因此，需要针对杜氏嗜血杆菌的替代疗法。在人类感染期间，杜氏杆菌在细胞外居住在专业吞噬细胞包围的环境中，包括中性粒细胞，这是先天免疫反应的关键组成部分。当不能吞噬细胞外病原体时，中性粒细胞经历新描述的过程，挤出染色质纤维，染色质纤维装饰着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外陷阱(Net)，可以诱捕细菌，然后这些细菌会被抗菌成分杀死。关于细菌病原体如何克服网络介导的杀戮，人们知之甚少。虽然杜氏嗜血杆菌的发病机制表明，在杜氏嗜血杆菌感染过程中可能会形成网络，但这种重要的人类病原体与网络的相互作用尚未被研究。该项目的长期目标是了解杜氏嗜血杆菌的净耐药机制，以便开发针对这些净耐药机制的新型抗菌剂。我们假设网络形成是对杜氏杆菌的反应，但病原体在体内有存活网络形成的机制。我们的初步数据表明，杜氏隐翅虫可能通过新的机制存活下来。这一应用的目的是确定杜氏嗜血杆菌感染过程中Nets的存在，在体内定位相对于Nets的杜氏嗜血杆菌，并确定杜氏嗜血杆菌对网络介导的杀伤的易感性。这些研究将建立一个系统来定义病原体抵抗网络介导的杀戮的新机制。这种机制可能会成为新型治疗药物的有用靶点，以对抗软下巴和可能的其他细胞外细菌感染。 与公共卫生相关：引起下巴的杜雷氏嗜血杆菌是一种重要的病原体，因为它有能力促进艾滋病毒的传播，并与艾滋病毒在地方性下巴流行地区的传播有很强的相关性。这项申请中的工作将定义H.ducreyi如何与人类中性粒细胞相互作用以生存下来，这是中性粒细胞用来在细胞外杀死病原体的主要机制。了解杜氏杆菌是如何克服中性粒细胞攻击的，将为开发抗击杜氏杆菌和其他人类细胞外病原体的改进疗法提供必要的信息。