HEMOLYSIN AND IMMUNOBIOLOGY OF CHANCROID

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。软下疳是一种常见的由杜氏嗜血杆菌引起的生殖器溃疡疾病，在一些发展中国家很常见，与艾滋病毒的异性传播有关。在美国，软下疳与艾滋病毒感染高危人群的地方性疾病有关。该项目的目标是了解杜克雷伊氏杆菌致病的机制，这一发现将使科学家能够设计出疫苗和其他预防策略。我们假设杜氏嗜血杆菌产生的两种毒素在这种生物体破坏宿主组织、逃避宿主免疫反应和在被感染个体中持续存在的能力中是重要的。为了探索这一假设，我们正在研究感染这种有机体的灵长类动物对杜克雷伊嗜血杆菌的特异性免疫反应。此外，我们正在比较两种杜克雷伊氏杆菌菌株（一种产生毒素，另一种不产生毒素）在灵长类动物感染模型中引起溃疡和存活的能力。在过去的一年里，我们构建了一个缺乏这两种毒素的突变株，并将该突变株和野生型菌株接种到四只灵长类动物身上，发现突变株在造成的病变中存在生存缺陷。我们随后修复了突变体的缺陷，目前正在确定是否恢复了毒力，希望能确认突变体的存活率下降仅仅是由于毒素基因，而不是另一个偶然的突变。考虑到在其他动物模型中使用类似突变体进行的实验没有显示出效果，这些实验尤其重要，这可能反映了宿主对这些毒素的特异性。最后，我们正在完成体液抗体反应（可检测到，但低于预期）、感染诱导的局部细胞因子（IFNgamma gt IL4）和感染诱导的细胞浸润的分析。

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.