Chancroid Human Challenge Unit (CHCU)

软下疳人类挑战单元 (CHCU)

• 批准号: 7962282
• 负责人: Stanley M. Spinola
• 金额: $ 18.28万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962282
• 关键词: Adherence; Adult; Africa; Antibiotic Resistance; Antibiotics; Antibodies; Asia; Attenuated; Bacteria; Bacterial Outer Membrane Proteins; Biology; Ceftriaxone; Cells; Clinical Trials; Collagen; Data; Dendritic Cells; Development; Disease; Disease Progression; Failure; Family suidae; Fibrin; Fibrinogen; Funding; Genes; Genital system; Genome; Goals; HIV; HIV-1; Heme Iron; Hemoglobin; Hemophilus ducreyi; Histopathology; Human; Human Volunteers; Immune response; Immunity; Immunization; Infection; Infection prevention; Lactamase; Latin America; Lead; Lesion; Local Microbicides; Macrolides; Modeling; National Institute of Allergy and Infectious Disease; Organism; Outcome; Parents; Pathogenesis; Phase; Plasmids; Predisposition; Proteins; Quinolones; Regulon; Research; Research Personnel; Resistance; Resources; Role; Safety; Secure; Series; Serum; Sexually Transmitted Diseases; Sigma Factor; Simulate; Site; Skin; Staging; Stress; System; T-Lymphocyte; Testing; Transcript; Treatment Protocols; U-Series Cooperative Agreements; Ulcer; United States; Upper arm; Vaccines; Virulence; Virulent; clinical phenotype; design; effective therapy; fighting; healthy volunteer; heme receptor; in vivo; in vivo Model; macrophage; mutant; neutrophil; quinolone resistance; quorum sensing; receptor; research study; resistance factors; response; success; transmission process; uptake; vaccine candidate; volunteer

Haemophilus ducreyi causes chancroid, a genital ulcer disease that facilitates HIV-1 transmission. Although rare in the United States, chancroid persists in Africa, Asia and Latin America. H. ducreyi has acquired many antibiotic resistance factors, and the only effective treatment regimens are macrolides, quinolones or ceftriaxone. If H. ducreyi acquires plasmids that encode extended spectrum p-lactamases and quinolone resistance, macrolides will be the only available therapy. Thus, understanding the pathogenesis of H. ducreyi remains important for the development of alternative strategies for control of chancroid. Most of what is known about H. ducreyi pathogenesis is derived from experiments in which human volunteers are inoculated on the arm with strain 35000HP. The human model mimics chancroid through the pustular stage of disease. The relationships between H. ducreyi and host cells are similar in natural and experimental infection, confirming that the model is highly relevant to natural disease. The model discriminates among virulent, partially attenuated and fully attenuated mutants of 35000HP and has helped identify the hemoglobin receptor, HgbA, as a rationale vaccine candidate. Analyses done by the Biostatistical Core led to the exciting discovery that humans are differentially susceptible to H. ducreyi infection; differentially susceptibility is associated with distinct dendritic cell responses to the organism. Project 2 seeks to continue a unique series of human inoculation experiments in the Chancroid Human Challenge Unit. Clinical trials such as those proposed in Project 2 can only be supported by U01 or U19 mechanisms, and Project 2 fulfills the broad collaborative goal of the STI CRC network by serving multiple investigators who lead STI CRC projects, ROIs, R21s, KOBs or need preliminary data to secure funding. The specific aims of Project 2 are to 1) test isogenic mutant/parent pairs to evaluate hypotheses concerning the contribution of candidate virulence determinants to disease progression, 2) infect volunteers with the parent strain to test hypotheses about H. ducreyi pathogenesis, host responses and differential human susceptibility to infection and 3) perform phase l/ll proof of concept safety and correlates of immunity studies of candidate vaccines.

杜克雷嗜血杆菌引起软下疳，这是一种生殖器溃疡疾病，有助于HIV-1传播。虽然 软下疳在美国很少见，但在非洲、亚洲和拉丁美洲却很常见。H. ducreyi获得了 许多抗生素耐药因素，唯一有效的治疗方案是大环内酯类，喹诺酮类或 头孢曲松。如果H. ducreyi获得了编码超广谱β-内酰胺酶和喹诺酮的质粒 耐药性，大环内酯类将是唯一可用的治疗方法。因此，了解H.杜克雷 对于开发控制软下疳的替代策略仍然很重要。的大部分地区都 了解H。杜克雷氏病的发病机理来自于人类志愿者接种的实验， 手臂上的应变35000 HP。人类模型模拟软下疳通过疾病的脓疱阶段。 H. ducreyi和宿主细胞在自然和实验感染中是相似的， 证实了该模型与自然疾病高度相关。该模型区分毒性， 35000 HP的部分减毒和完全减毒突变体，并有助于鉴定血红蛋白 HgbA受体作为一个合理的疫苗候选人。生物统计核心进行的分析导致 令人兴奋的发现是人类对H.杜克雷感染;差异易感性 与树突状细胞对生物体的不同反应有关。项目2旨在继续一个独特的 在软性下疳人体挑战装置中进行的一系列人体接种实验。临床试验，如 项目2中提出的那些只能由U 01或U19机制支持，项目2满足了 通过为领导STI CRC的多名研究者提供服务，实现STI CRC网络的广泛合作目标 项目、ROI、R21、KOB或需要初步数据以获得资金。项目2的具体目标是 1)测试同基因突变体/亲本对，以评估关于候选基因的贡献的假设。 疾病进展的毒力决定因素，2）用亲本菌株感染志愿者以检验假设 关于H. ducreyi发病机制，宿主反应和人类对感染的不同易感性，以及3） 进行候选疫苗的概念安全性和免疫相关性研究的I/II期验证。