Experimental Infection of Human Volunteers withHaemophilus ducreyi:Fifteen Years of Clinical Data and Experience

Abstract

Haemophilus ducreyi causes chancroid, which facilitates transmission of HIV-1. To better understand the biology of H. ducreyi, we developed a human inoculation model. Here, we describe the clinical outcomes of 267 volunteers who were infected with H. ducreyi. There was a relationship between papule formation and dose. The outcome (pustule formation or resolution) of infected sites within a subject was not independent; the most important determinants of pustule formation were gender and host. When infected a second time, subjects (n = 41) segregated towards their initial outcome, confirming the host effect. Subjects with pustules developed local symptoms, requiring termination from the study after a mean of 8.6 days. Hypertrophic scars developed in 16.2% of volunteers who were biopsied, but the model was otherwise safe. Mutant-parent trials confirmed key features in H. ducreyi pathogenesis, and the model has provided an opportunity to study differential human susceptibility to a bacterial infection.

Activation of the CpxRA System by Deletion of cpxA Impairs the Ability of Haemophilus ducreyi To Infect Humans

“…A major function of CpxRA is to control protein traffic across the cytoplasmic membrane. Several OMPs, including DsrA, HgbA, NcaA, and PAL, are required for virulence in humans (24). To discern whether activation of CpxR affected the expression of OMPs, we compared the OMP profiles of 35000HP⌬cpxA and 35000HP.…”

“…Subjects gave informed consent for participation and for HIV serology, in accordance with the human experimentation guidelines of the U.S. Department of Health and Human Services and the Institutional Review Board of Indiana University-Purdue University of Indianapolis. The experimental challenge protocol, preparation and inoculation of the bacteria, calculation of the estimated delivered dose (EDD), clinical observations, surface cultures, definitions of clinical endpoints, biopsies, and antibiotic treatment of the volunteers were carried out exactly as described previously (24). To account for the correlation among sites within the same individual, comparison of papule and pustule formation rates for the two strains were performed using a logistic regression model with generalized estimating equations (GEE), as described previously (37).…”

“…To determine how H. ducreyi causes infection, we developed a human inoculation model in which strain 35000HP (HP, human passaged) and its derivatives are inoculated into the skin of the arm of healthy adult volunteers via puncture wounds (24). Papules develop within 24 h and either spontaneously resolve or evolve into pustules within 2 to 5 days, simulating natural infection.…”

Haemophilus ducreyi-Induced Interleukin-10 Promotes a Mixed M1 and M2 Activation Program in Human Macrophages

“…To study the immunopathogenesis of H. ducreyi infection, we developed a human challenge model in which the skin of the upper arm of healthy adult volunteers is inoculated with H. ducreyi strain 35000HP or its derivatives (21,46,47). Papules form within 24 h of inoculation and either spontaneously resolve or evolve into pustules within 2 to 5 days, mimicking the early stages of natural infection.…”

Haemophilus ducreyi RpoE and CpxRA Appear To Play Distinct yet Complementary Roles in Regulation of Envelope-Related Functions

“…The papules eventually develop into pustules, which finally erode into painful ulcers. To understand how H. ducreyi causes infection in its natural host, our laboratory developed a human challenge model of infection (7). In this model, healthy adult volunteers are inoculated with H. ducreyi on the skin of the upper arm via puncture wounds.…”