Haemophilus ducreyi causes chancroid, a genital ulcer disease that facilitates HIV-1 transmission. Although rare in the United States, chancroid persists in Africa, Asia and Latin America. H. ducreyi has acquired many antibiotic resistance factors, and the only effective treatment regimens are macrolides, quinolones or ceftriaxone. If H. ducreyi acquires plasmids that encode extended spectrum p-lactamases and quinolone resistance, macrolides will be the only available therapy. Thus, understanding the pathogenesis of H. ducreyi remains important for the development of alternative strategies for control of chancroid. Most of what is known about H. ducreyi pathogenesis is derived from experiments in which human volunteers are inoculated on the arm with strain 35000HP. The human model mimics chancroid through the pustular stage of disease. The relationships between H. ducreyi and host cells are similar in natural and experimental infection, confirming that the model is highly relevant to natural disease. The model discriminates among virulent, partially attenuated and fully attenuated mutants of 35000HP and has helped identify the hemoglobin receptor, HgbA, as a rationale vaccine candidate. Analyses done by the Biostatistical Core led to the exciting discovery that humans are differentially susceptible to H. ducreyi infection;differentially susceptibility is associated with distinct dendritic cell responses to the organism. Project 2 seeks to continue a unique series of human inoculation experiments in the Chancroid Human Challenge Unit. Clinical trials such as those proposed in Project 2 can only be supported by U01 or U19 mechanisms, and Project 2 fulfills the broad collaborative goal of the STI CRC network by serving multiple investigators who lead STI CRC projects, ROIs, R21s, KOBs or need preliminary data to secure funding. The specific aims of Project 2 are to 1) test isogenic mutant/parent pairs to evaluate hypotheses concerning the contribution of candidate virulence determinants to disease progression, 2) infect volunteers with the parent strain to test hypotheses about H. ducreyi pathogenesis, host responses and differential human susceptibility to infection and 3) perform phase l/ll proof of concept safety and correlates of immunity studies of candidate vaccines.