HEMOLYSIN AND IMMUNOBIOLOGY OF CHANCROID

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chancroid, a genital ulcer disease common caused by Haemophilus ducreyi, is common in several developing countries where it is associated with the heterosexual transmission of HIV. In the United States, chancroid is associated with endemics in populations at high risk for HIV infection. The goal of this project is to understand the mechanisms by which H. ducreyi causes disease, a finding that would allow scientists to devise vaccines and other strategies for prevention. We hypothesize that two toxins produced by H. ducreyi are important in the ability of this organism to damage host tissue, evade the host immune response, and persist in infected individuals. To explore this hypothesis, we are studying the specific immune response to H. ducreyi in primates infected with this organism. In addition, we are comparing the ability of two H. ducreyi strains, one that produces toxins and one that does not, to cause ulcers and survive in the primate model of infection. In the past year, we had completed our construction of a mutant strain of H. ducreyi lacking the two toxins, inoculated this mutant as well as the wild type strain into four primates and found that the mutant was defective in survival in resulting lesions. We subsequently repaired the defect in the mutant and are currently determining whether virulence is restored, hopefully confirming that the mutant's decreased survival was due solely to the toxin genes and not another fortuitous mutation. These experiments are particularly significant, given that experiments with similar mutants in other animal models showed no effect, possibly reflecting the host specificity for these toxins. Finally, we are completing our analysis of the humoral antibody response (detectable, but lower than expected), local cytokines induced by infection (IFNgamma gt IL4), and the cellular infiltration induced by infection.