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

项目摘要 这份K23申请由Andrea A. Berry，医学博士，儿科助理教授， 马里兰州大学医学院。贝瑞博士的长期目标是成为一名独立的调查员 在疟疾转化研究领域。为了实现这一目标，她提出了一个指导性的职业发展， 该计划提供微阵列分析、生物统计学和流行病学方面的培训。 一种有效的恶性疟原虫疟疾疫苗将提高控制和最终控制疟疾的前景。 消灭疟疾。然而，该领域才刚刚开始了解其要求和特点 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方法 在高通量蛋白质微阵列上进行分析，可以阐明对数百种P. 恶性疟原虫抗原变体。研究小组使用蛋白质微阵列， 关键恶性疟原虫抗原的不同变体，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，知识的差距是区分能力 由于交叉反应性引起的抗体结合和由于累积暴露于疟疾引起的抗体结合之间的差异 - 在蛋白质微阵列上，两种反应都表现为对多种抗原变体的反应性。区分 这两种抗体结合模式在田间研究中是困难的， 参与者以前的暴露，即使是正在进行的感染，也不能总是知道确切的基因 寄生虫的组成或暴露的确切时间。阐明交叉反应性的特征， 然而，累积的暴露对于更好地了解 对疟疾的保护性免疫。 受控制的人类疟疾感染，志愿者通过感染性疾病的叮咬接触疟疾。 蚊子，是一个机会来研究单克隆疟疾感染对免疫反应的影响。 这项拟议的工作将评估疟疾初治志愿者的免疫反应， 反复感染恶性疟原虫，以告知个人生活中的免疫反应的解释， 在疟疾流行地区。蛋白质和肽微阵列将用于探测来自最初幼稚的 志愿者从恶性疟原虫攻击中恢复后。 目的1：通过比较两组志愿者，评价单一感染对免疫应答的影响 感染了两种不同的恶性疟原虫 目的2：通过对一组志愿者的随访，评价重复感染对免疫应答的影响 两年内感染了四次恶性疟原虫。

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.