Neutrophil Extracellular Traps and Haemophilus ducreyi

描述（由申请方提供）：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疾病，可促进人类免疫缺陷病毒（HIV）的传播和获得，从而促进HIV在地方性软下疳地区的传播。H. ducreyi菌株极大地缩小了治疗软下疳的药物选择;因此，针对H.需要ducreyi。在人类感染过程中，H. Ducreyi存在于由专职吞噬细胞（包括中性粒细胞，先天免疫应答的关键组分）包围的细胞外环境中。当不能吞噬细胞外病原体时，中性粒细胞经历新近描述的从中性粒细胞颗粒中挤出染色质纤维的过程，所述染色质纤维被抗菌成分装饰。这些基于DNA的结构，称为中性粒细胞胞外陷阱（NET），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介导的杀伤作用知之甚少。虽然H. ducreyi认为NET的形成可能发生在H. ducreyi感染，这种重要的人类病原体与NET的相互作用尚未研究。本项目的长期目标是了解H. ducreyi，以便可以开发针对这些NET耐药机制的新型抗菌剂。我们假设NET的形成是对H. ducreyi，但病原体具有在体内形成NET后存活的机制。我们的初步数据表明，H。ducreyi可能通过新的机制在NET中存活。本申请的目的是确定在H. ducreyi感染，局部H. ducreyi相对于NETs在体内，并定义H的易感性。ducreyi至NET介导的杀伤。这些研究将建立一个系统，用于定义病原体抵抗NET介导的杀伤的新机制。这些机制将可能作为新的治疗药物的有用的目标，以打击软下疳和其他可能的细胞外细菌感染。 公共卫生相关性：杜克雷嗜血杆菌引起软下疳，是一种重要的病原体，因为它能够促进艾滋病毒的传播，并与地方性软下疳地区艾滋病毒的传播密切相关。在这个应用程序中的工作将定义如何H。ducreyi与人嗜中性粒细胞相互作用以存活，这是嗜中性粒细胞用于细胞外杀死病原体的主要机制。了解H。ducreyi克服中性粒细胞攻击将提供必要的信息，以开发改进的治疗方法，以打击H。ducreyi和其他人类细胞外病原体。

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.