Neutrophil Extracellular Traps and Haemophilus ducreyi

描述（由申请人提供）：杜氏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疾病，容易传播和获得人类免疫缺陷病毒（HIV），从而导致艾滋病毒在地方性软下疳地区传播。杜克雷伊杆菌菌株中抗生素耐药性的增加大大缩小了治疗软下疳的药物选择；因此，需要替代疗法来对抗杜克雷伊嗜血杆菌。在人类感染过程中，杜氏嗜血杆菌存在于被专业吞噬细胞包围的细胞外环境中，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挤出染色质纤维的过程，这些染色质纤维由中性粒细胞颗粒中的抗菌成分装饰。这些基于dna的结构，被称为中性粒细胞细胞外陷阱（NETs），可以诱捕细菌，然后被抗菌成分杀死。关于细菌病原体如何克服net介导的杀伤作用，我们所知甚少。虽然杜氏嗜血杆菌的发病机制表明，NET的形成可能发生在杜氏嗜血杆菌感染期间，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耐净叶杆菌耐药机制，以便开发针对这些耐净叶杆菌耐药机制的新型抗菌药物。我们假设NET的形成是对H. ducreyi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可能通过新的机制在net中存活。本应用程序的目的是确定net在H. ducreyi感染期间的存在，定位体内相对于net的H. ducreyi，并确定H. ducreyi对net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net介导的杀伤的新机制。这种机制很可能成为对抗软下疳和其他细胞外细菌感染的新型治疗药物的有用靶点。

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.