Haemophilus ducreyi is the etiologic agent of chancroid, a genital ulcer disease that facilitates transmission of the Human Immunodeficiency Virus (HIV) in populations where both infections are endemic. A vaccine to prevent chancroid may be important in efforts to limit the spread of H. ducreyi and HIV infections in chancroid endemic areas. Characterization of the human immune response to H. ducreyi is critical information that is needed for vaccine development. Our understanding of the immune responses to H. ducreyi has been hampered by a total lack of longitudinally collected clinical specimens from naturally infected patients. H. ducreyi is a strict human pathogen that expresses cell surface components that mimic human antigens. To study the pathogenesis of chancroid, we have developed an experimental model of skin infection in human volunteers. The course of experimental infection mimics naturally occurring disease. The focus of this application is to develop and study the model so that we can test hypotheses about host immune responses to H. ducreyi. In the experimental model, papular lesions may either spontaneously resolve or progress to pustule formation. Our data suggests that the outcome of infection is modulated by local factors. This is the first evidence that the human host can mount an effective immune response to H. ducreyi. The focal point of the immune response is a cutaneous infiltrate of CD4+ cells. The outcome of a variety of infections depends on production of cytokines that affect the equilibrium between the TH1 and TH2 cell populations at sites of disease. Whether the CD4+ cells present in the experimental lesions are TH1, TH2 or mixed is unknown. Our first hypothesis is that the T cell infiltrate and cytokines produced in the experimental lesions change over time and influence the outcome of infection in the model. Our second hypothesis is that H. ducreyi antigens specifically elicit the cutaneous T cell responses in the model. To test these hypotheses, our specific aims include: standardization of the human challenge model of experimental H. ducreyi infection; immunohistopathological and cytokine analysis of experimental lesions biopsied at different times during the course of infection; recovery of T cell clones from experimental lesions; characterization of the response of the T cell clones to H. ducreyi antigens.
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