Protein microarray antibody responses to P. falciparum in a human challenge model

项目总结 这份K23申请是由安德里亚·A·贝里医学博士提交的，她是哈佛大学儿科学助理教授 马里兰大学医学院。贝瑞博士的长期目标是成为一名独立调查员 在疟疾翻译研究领域。为了实现这一目标，她提出了一种有指导的职业发展 提供微阵列分析、生物统计学和流行病学培训的计划。 一种有效的恶性疟疾疫苗将提高控制和最终治愈疟疾的前景 根除疟疾。然而，该领域才刚刚开始了解需求和特点 疟疾保护性免疫，这是疫苗开发的关键。一种有希望的方法是血清学 在高通量蛋白质芯片上的图谱分析，可以阐明对数百种P。 恶性疟原虫抗原变异体同时发生。研究小组使用了蛋白质微阵列，其中包含 恶性疟原虫关键抗原的不同变体，以便他们可以研究与交叉感染相关的抗原变体 反应性和交叉保护性免疫反应。然而，知识的差距是区分的能力。 交叉反应引起的抗体结合和疟疾累积暴露引起的抗体结合之间的关系 -在蛋白质微阵列上，这两种反应都表现为对多种抗原变体的反应。差异化 这两种抗体结合模式在现场研究中是困难的，因为只有有限的数据可用于 参与者以前的接触情况，即使是持续感染，也不能总是知道确切的基因 寄生虫的组成或接触的确切时间。阐明了交叉反应的特点和 然而，积累的接触对于更好地了解糖尿病的发展至关重要 对疟疾的保护性免疫。 控制人类疟疾感染，志愿者通过被传染性疾病叮咬而暴露在疟疾中 蚊子是研究单克隆性疟疾感染对免疫反应影响的机会。 这项拟议的工作将评估疟疾天真志愿者的免疫反应，这些志愿者经历了单身和 反复感染恶性疟原虫，以便解释活着的个体的免疫反应 在疟疾流行地区。蛋白质和多肽芯片将被用来探测最初天真的血清 志愿者从恶性疟原虫的挑战中恢复过来。 目的1：通过对两组志愿者的比较，评价单一感染对免疫应答的影响 感染两种不同的恶性疟原虫株后。 目的2：通过跟踪一组志愿者，评价反复感染对免疫应答的影响 他们在两年内经历了四次恶性疟原虫感染。

PROJECT SUMMARY This K23 application is submitted by Andrea A. Berry, M.D., an Assistant Professor of Pediatrics at the University of Maryland School of Medicine. Dr. Berry's long term goal is to become an independent investigator in the field of malaria translational research. Towards this goal, she proposes a mentored career development plan that provides training in microarray analysis, biostatistics, and epidemiology. An effective Plasmodium falciparum malaria vaccine will boost prospects for the control and eventual eradication of malaria. However, the field is only beginning to understand the requirements and characteristics of malaria protective immunity, which is key to vaccine development. A promising approach is serological profiling on high-throughput protein microarrays, which can elucidate antibody responses to hundreds of P. falciparum antigen variants simultaneously. The investigator's group uses protein microarrays containing diverse variants of key P. falciparum antigens so that they can study antigen variants associated with cross- reactive and cross-protective immune responses. However, a gap in knowledge is the ability to differentiate between antibody binding due to cross-reactivity and antibody binding due to accumulated exposure to malaria – on protein microarrays, both responses manifest as reactivity to multiple antigen variants. Differentiating these two patterns of antibody binding is difficult in field studies because only limited data is available on participants' previous exposure, and even for ongoing infections one cannot always know the exact genetic makeup of the parasite or the exact timing of exposure. Elucidating the characteristics of cross-reactivity and accumulated exposure is nonetheless critical to gaining a better understanding of the development of protective immunity from malaria. Controlled Human Malaria Infections, in which volunteers are exposed to malaria through the bites of infectious mosquitoes, are an opportunity to study the effect of single-clone malaria infections on the immune response. This proposed work will evaluate immune responses in malaria naïve volunteers who experience single and repeated P. falciparum infections in order to inform the interpretation of immune responses in individuals living in malaria endemic regions. Protein and peptide microarrays will be used to probe sera from initially naïve volunteers after they have recovered from P. falciparum challenge. Aim 1: Evaluate the effect of single infections on the immune response by comparing two groups of volunteers after infection with two different P. falciparum strains. Aim 2: Evaluate the effect of repeated infection on the immune response by following a group of volunteers who experience four P. falciparum infections over two years.