Protective immunity induced by P. yoelii genetically attenuated vaccines

描述(申请人提供)：我们工作的长期目标是开发一种成功的抗疟疾疫苗。疟疾的负担说明了这种疫苗的紧迫性，每年有多达200万人死于恶性疟原虫感染。特别是，我们在这里建议研究对小鼠红细胞期前寄生虫的保护性免疫的免疫学基础，这是通过用不同的基因减毒寄生虫(GAP)免疫小鼠而产生的。因此，了解保护性免疫涉及的机制可以为合理设计和开发有效的疟疾疫苗奠定基础。初步数据表明，LS寄生虫可能是保护性免疫的主要靶点，LS蛋白也有助于GAP疫苗诱导保护性免疫。以约氏疟原虫GAP(PyGAP)为模型，我们证明了一种遗传缺陷寄生虫[Pyuis4(-)]比另一种[Pyuis3(-)]诱导的保护性免疫更强、持续时间更长，并且不同GAP免疫的小鼠识别不同的抗原。基于这些数据，我们推测，不同的GAP引起的保护性免疫的变化可能涉及不同的免疫介质，以及区分保护性和非保护性免疫、短期免疫和长期免疫的免疫生物标志物和靶抗原的不同特征。在这个项目中，我们建议通过三个目标来验证我们的假设：在目标1中，我们将建立一个系统的保护性免疫模型，在三种不同的PyGAP和irr-SPZ免疫之后，这三种免疫代表了一系列的保护性免疫-针对野生型约氏疟原虫的子孢子攻击的完全长期免疫、部分和短期免疫或非保护性免疫。然后，我们可以表征T细胞的反应(大小，表型和增殖)与不同程度和持续时间的保护性免疫相关的不同品系的小鼠。在目标2中，我们将确定与不同的PyGAP诱导的不同保护性免疫相关的独特的免疫生物标志物。目的3阐明PyGAP诱导的CD8T细胞保护性反应的效应机制。这项研究的结果，对于更好地理解T细胞介导的免疫，识别抗疟疾感染的免疫生物标志物，以及PyGAP疫苗诱导的保护性免疫的效应机制，将对开发有效的亚单位疟疾疫苗具有重要价值。

DESCRIPTION (provided by applicant): The long term goal of our work is to develop a successful anti-malaria vaccine. The burden of malaria, with up to two million deaths per year due to Plasmodium falciparum infection, illustrates the urgency for such a vaccine. In particular, we propose herein to study the immunological basis for the protective immunity against pre-erythrocytic stage parasites that is induced by immunizations with distinct genetically attenuated parasite (GAP) in mice. Understanding the mechanisms involved in protective immunity could then provide the foundation for rational design and development of an effective malaria vaccine. Preliminary data indicate that LS parasites may be the predominant targets of protective immunity and that LS proteins also contribute to the induction of protective immunity induced by GAP vaccines. Using P. yoelii GAPs (PyGAP) as model, we demonstrated that one genetically deficient parasite [Pyuis4(-)] induced more potent and prolonged protective immunity than another [Pyuis3(-)], and that mice immunized with different GAPs recognized different antigens. Based on these data, we hypothesize that the variation in protective immunities induced by different GAPs may involve different immune mediators and a divergent profile of immune biomarkers and target antigens that distinguish protective from non-protective, and short-lived from long-lived, immunity. In this project, we propose to test our hypothesis via three aims: In aim 1, we will establish a systematic model of protective immunity following three different PyGAPs and irr-spz immunization that represent a range of protective immunity - complete long-lasting, partial and short-lived, or non-protective immunity against wild type P. yoelii sporozoite challenge. We can then characterize T cell responses (magnitude, phenotypes and proliferation) associated with the different degrees and durations of protective immunity in different trains of mice. In Aim 2, we will determine the distinctive immune biomarkers that associate with differentially protective immunity induced by different PyGAPs. Aim 3 will delineate the effector mechanisms of protective CD8 T cell responses induced by PyGAP. The outcome of this study, a better understanding of the T cell-mediated immunity, identification of immune biomarkers of protection against malaria infection, and effector mechanisms of protective immunity induced by PyGAP vaccines, will be invaluable for development of an effective subunit malaria vaccine.