Haemophilus ducreyi causes chancroid, a genital ulcer disease (GUD) that facilitates HIV transmission and acquisition. Lacking clinical specimens, we developed a human challenge model in which H. ducreyi is inoculated into the skin of the upper arm in volunteers. In the model, the kinetics of papule and pustule formation resemble naturally occurring infection, and the cutaneous infiltrate is almost identical to that seen in naturally occurring ulcers. We have infected 202 subjects, 30 of whom were infected twice, in several types of clinical trials in collaboration with many STI investigators outside our CRC. Three volunteers who were HIV-seropositive were infected in an ongoing Phase 1 trial to study H. ducreyi-HIV interactions. The model was used to explore the role of putative virulence determinants in disease, expression of bacterial genes in vivo, the cutaneous immune response to the organism, how the bacteria interacts with host cells, and gender and subject effects on susceptibility to disease progression. This project is a renewal of the Chancroid Human Challenge Unit (CHCU) within the Midwest STI TM CRC. Our goal is to continue to perform high quality clinical trials in human volunteers. With the completion of the H. ducreyi genome project, we and our collaborators have the unique opportunity to simultaneously evaluate hypotheses about host responses and virulence determinants at an actual site of human infection, in addition, we will test hypotheses about interactions between H. ducreyi and HIV that drive viral acquisition and transmission. We will examine whether the macrophages and T cells recruited to the skin in HIV-seronegatives are susceptible to viral infection. We will also test whether H. ducreyi promotes HIV replication via activation of latently infected CD4 CD45RO cells in the lesions by infecting stable, immunocompetent HIV seropositives with H. ducreyi. These studies will be among the first to directly address the effect of an STI on HIV replication in a longitudinal fashion, an area of priority in the RFA. This project maintains two longstanding themes of the Midwest Center: agents of GUD and collaboration with other STI investigators.
Our specific aims i nclude: (1) to explore interactions between H. ducreyi and HIV by study of samples obtained from infection of both HIV seropositive and seronegative subjects; (2) to test isogenic mutant/parent pairs in the model to evaluate the contribution of candidate virulence determinants to papule and pustule formation; (3) to infect subjects with the parent strain to facilitate and extend studies of pathogenesis and the local host response.
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