Mechanisms of Immune Avoidance by Haemophilus ducreyi

描述（由申请人提供）：软下疳是一种在撒哈拉以南非洲和东亚流行的细菌性生殖器溃疡疾病。ducreyi嗜血杆菌（软下疳的病原体）的免疫反应在清除受感染个体的生物体或防止随后的ducreyi嗜血杆菌再次感染方面都不是很有效。本文描述的三个具体目标旨在利用和扩展下疳猪模型来测试与这种不良免疫反应机制相关的假设。目的1通过验证杜克雷伊氏嗜血杆菌主要引起细胞免疫的假设来评估宿主对杜克雷伊氏嗜血杆菌的反应，而细胞免疫对清除感染细菌无效。从感染的病变中分离的H. ducreyi特异性CD4和CD8淋巴细胞的细胞因子表达模式将被检测。在目标2中，细菌对抑制免疫反应的贡献将通过测试假设来解决，即H. ducreyi CDT和溶血素毒素通过其对免疫效应细胞的细胞毒性作用来阻断免疫发展。这一目标将通过比较接种cdt/hem双突变体和野生型杜氏嗜血杆菌后免疫发育的动力学和强度来实现，同时也评估突变体影响的T细胞细胞因子表达和抗原特异性与野生型生物体相比的差异。毒素对免疫反应的具体作用将通过测试它们对抗体和细胞毒性T细胞对鸡蛋溶菌酶的影响来检验。目的2提出了一种假设，即对杜克雷伊氏杆菌产生强有力的杀菌抗体反应将导致更有效地清除感染组织中的生物体，并防止随后的杜克雷伊氏杆菌再感染。已鉴定出一种可作为杀菌抗体靶点的杜氏嗜血杆菌外膜蛋白。该蛋白将被测试是否能引发对杜克雷伊嗜血杆菌的保护性免疫反应。

DESCRIPTION (provided by applicant): Chancroid is a bacterial genital ulcer disease endemic to sub-Saharan Africa and Eastern Asia. The immune response to Haemophilus ducreyi, the etiologic agent of chancroid, is not very effective at either clearing organisms from an infected individual or at preventing subsequent H. ducreyi re-infections. The three specific aims described herein are designed to utilize and extend the swine model of chancroid to test hypotheses that relate to the mechanisms underlying this poor immune response. Aim 1 assesses the host response to H. ducreyi by testing the hypothesis that H. ducreyi elicit predominantly cellular immunity, which is ineffective at clearing the infecting bacteria. The cytokine expression pattern of H. ducreyi specific CD4 and CD8 lymphocytes isolated from infected lesions will be examined. In Aim 2 the bacterial contribution to inhibiting the immune response will be addressed by testing the hypothesis that the H. ducreyi CDT and hemolysin toxins block immunity development through their cytotoxic effect on immune effector cells. This aim will be accomplished by comparing the kinetics and strength of immune development following inoculation with cdt/hem double mutants and wild type H. ducreyi, while also assessing differences in T cell cytokine expression and antigen specificity effected by mutant as compared to wild type organisms. The specific contribution of the toxins on the immune response will be examined by testing their effect on the development of antibody and cytotoxic T cells to hen egg lysozyme. Aim 2 addresses the hypothesis that a vigorous bactericidal antibody response to H. ducreyi would result in more efficient clearing of organisms from infected tissue and prevent subsequent H. ducreyi re infection. An H. ducreyi outer membrane protein that is a target for bactericidal antibody has been identified. This protein will be tested for the ability to elicit a protective immune response to H. ducreyi.