Molecular pathogenesis of Haemophilus ducreyi infection in human volunteers

SUMMARYHaemophilus ducreyi is a Gram-negative coccobacillus that forms a distinct lineage with Aggregatibacter pleuropneumoniae and Mannheimia haemolytica within the Pasteurellaceae. H. ducreyi causes chancroid, which is characterized by painful genital ulcers (GU) and inguinal lymphadenitis, and facilitates the transmission of HIV. Although once thought to be exclusively sexually transmitted, H. ducreyi is now recognized as a major cause of non-sexually transmitted cutaneous ulcers (CU) on the lower legs of children who live in yaws-endemic areas. Due to the impact of chancroid on global health, the lack of human specimens, and the need to understand H. ducreyi pathogenesis, in 1993, we developed a model in which healthy adult volunteers are infected on the skin overlying the deltoid with the GU strain 35000HP and its isogenic mutants. This review summarizes 31 years of clinical experience with inoculating 429 unique participants and the behavior of strain 35000HP in the model. We examine sex and host effects on the outcome of initial inoculations and the results of second challenges of 53 participants, which together indicate that there is differential host susceptibility to infection, and explore the immunological basis for this phenomenon. We describe the evaluation of candidate bacterial virulence determinants in disease as determined in 38 mutant vs. parent comparison trials and the identification of potential vaccine candidates, which may be needed to control CU. We provide aggregate information on adverse events so that others can replicate this model. This review should also serve as a template for the ethical development of additional human infection models.