Haemophilus ducreyi, the etiologic agent of the genital ulcer disease chancroid, is an emerging bacterial pathogen in the United States. This organism has long been recognized as a significant sexually transmitted pathogen in other parts of the world, particularly in southeast Asia and Africa. Regardless of its world-wide prevalence, and the fact that H. ducreyi infections significantly enhance heterosexual HIV transmission, this organism is arguably the least understood of the sexually transmitted pathogens. The long-term goal of this project is to establish the basis for the unique aspects of H. ducreyi-host interactions, and thus a better understanding of how this organism causes disease and contributes to HIV transmission.
Specific Aim #1 : What is the pattern of host immune cell and cytokine response to H. ducreyi infection? This aim is based on the hypothesis that H. ducreyi initially interact with host keratinocytes provoking the expression of specific cytokines, IL-8 in particular, that contribute to chancroid pathogenesis. The investigators will examine the effects of this cytokine induction on PMN migration and bacterial activity against H. ducreyi in an artificial in vitro skin model of infection.
Specific Aim #2 : What host cells are associated with H. ducreyi and what are the host cell association mechanisms expressed by this pathogen? This aim is based on the hypothesis that H. ducreyi are present within the suprabasal keratinocytes in the host, and that specific products expressed by this organism promote adherence to, and invasion of, human keratinocytes. H. ducreyi-host cell associations will be examined in the artificial skin and swine infection models. A combination of genetic procedures including gene cloning and mutagenesis will be used to determine the pathogen-specific components required for H. ducreyi interactions with host cells.
Specific Aim #3 : How does the exported CuZn SOD contribute to H. ducreyi pathogenesis? The experiments in this aim test the hypothesis that the H. ducreyi exported CuZn SOD protects this organism from the bactericidal effects of host-generated superoxide. The relative survival of wild type and mutant H. ducreyi lacking the exported SOD exposed to neutrophils in the artificial skin model will be determined. The role of the exported SOS in H. ducreyi survival and lesion development will be evaluated in the swine model of chancroid using both normal and neutropenic pigs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG5-BM-1 (03))
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Hitchcock, Penelope
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Fulcher, Robert A; Cole, Leah E; Janowicz, Diane M et al. (2006) Expression of Haemophilus ducreyi collagen binding outer membrane protein NcaA is required for virulence in swine and human challenge models of chancroid. Infect Immun 74:2651-8
Cole, Leah E; Toffer, Kristen L; Fulcher, Robert A et al. (2003) A humoral immune response confers protection against Haemophilus ducreyi infection. Infect Immun 71:6971-7
Bong, Cliffton T H; Fortney, Kate R; Katz, Barry P et al. (2002) A superoxide dismutase C mutant of Haemophilus ducreyi is virulent in human volunteers. Infect Immun 70:1367-71
Cole, Leah E; Kawula, Thomas H; Toffer, Kristen L et al. (2002) The Haemophilus ducreyi serum resistance antigen DsrA confers attachment to human keratinocytes. Infect Immun 70:6158-65
San Mateo, L R; Toffer, K L; Orndorff, P E et al. (1999) Neutropenia restores virulence to an attenuated Cu,Zn superoxide dismutase-deficient Haemophilus ducreyi strain in the swine model of chancroid. Infect Immun 67:5345-51
San Mateo, L R; Toffer, K L; Orndorff, P E et al. (1999) Immune cells are required for cutaneous ulceration in a swine model of chancroid. Infect Immun 67:4963-7
Zaretzky, F R; Kawula, T H (1999) Examination of early interactions between Haemophilus ducreyi and host cells by using cocultured HaCaT keratinocytes and foreskin fibroblasts. Infect Immun 67:5352-60