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.
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.
