HEMOLYSIN AND IMMUNOBIOLOGY OF CHANCROID

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。软下疳是一种由杜克雷嗜血杆菌引起的常见生殖器溃疡疾病，在几个发展中国家很常见，在那里它与艾滋病毒的异性传播有关。在美国，软下疳与HIV感染高危人群的地方病有关。本项目的目标是了解H。ducreyi引起疾病，这一发现将使科学家能够设计疫苗和其他预防策略。我们推测H. ducreyi在该生物体破坏宿主组织、逃避宿主免疫应答和在感染个体中持续存在的能力方面是重要的。为了探索这一假说，我们正在研究对H.感染了这种生物的灵长类动物体内的ducreyi。此外，我们还比较了两个H。ducreyi菌株，一种产生毒素，一种不产生毒素，导致溃疡并在灵长类动物感染模型中存活。 在过去的一年中，我们已经完成了H.缺乏这两种毒素的ducreyi将该突变体以及野生型菌株接种到四种灵长类动物中，发现该突变体在所产生的损伤中的存活缺陷。我们随后修复了突变体中的缺陷，目前正在确定毒力是否恢复，希望证实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。这些实验特别重要，因为在其他动物模型中使用类似突变体的实验显示没有效果，可能反映了这些毒素的宿主特异性。最后，我们完成了对体液抗体反应（可检测，但低于预期）、感染诱导的局部细胞因子（IFN γ gt IL 4）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.