Memory CD8 T cell immunity to Plasmodium liver stage infec

 描述（由申请人提供）：由疟原虫属物种引起的疟疾疾病仍然是一个尚未解决的全球健康负担，影响着超过40%的世界人口。虽然杀虫剂处理过的蚊帐和抗疟疾药物的供应降低了一些地区疟疾的发病率和严重程度，但2013年每年仍有约2亿例疟疾病例，约85万人死亡。因此，预防疟疾的疫苗仍然是一个尚未实现的但对应对这一全球威胁至关重要的目标。 如我们的初步数据所示，只有一些引起CD 8 T细胞应答的疟原虫抗原是CD 8 T细胞介导的灭菌免疫的靶点。目的1将解决的机制，确定是否一个特定的疟原虫抗原是有效的保护记忆CD 8 T细胞的目标。从这一目标产生的信息将提供一个实用的基础，选择新的候选抗原，从约5,000个ORF的表达池，作为亚单位疫苗，以防止人类疟疾的评价。 重要的是，尽管反复暴露，但生活在疟疾流行地区的个体不会产生杀菌免疫（定义为预防子孢子感染后的血液阶段寄生虫血症）。事实上，我们的初步数据揭示了疟疾感染期间产生的记忆CD 8 T细胞的数量和功能受损。在目标2中，我们将使用我们新开发的工具箱，包括对最近鉴定的疟原虫抗原具有特异性的TCR逆转录小鼠，以确定疟疾感染后产生的记忆CD 8 T细胞在数量和功能上如何受损。 我们的长期目标是了解保护性CD 8 T细胞免疫肝脏阶段疟原虫感染的机制，以帮助合理开发有效的疫苗。SA 1.确定为什么一些，但不是所有的疟原虫抗原是保护性CD 8 T细胞的目标。SA 2.确定疟原虫感染导致记忆性CD 8 T细胞群受损的机制。

 DESCRIPTION (provided by applicant): Malarial disease, caused by Plasmodium species, remains an unresolved global health burden that impacts >40% of the world's population. Although the availability of insecticide treated bed nets and antimalarial drugs has reduced the incidence and severity of malaria in some regions, ~200,000,000 cases still occur annually with ~850,000 fatalities in 2013. Thus, vaccines to prevent malaria remain an as yet unrealized but critical goal to combat this global threat. As shown in our preliminary data, only some of Plasmodium antigens that elicit CD8 T cell responses were targets of CD8 T cell mediated sterilizing immunity. Aim 1 will address the mechanisms that determine whether a specific Plasmodium antigen is the target of effective protection by memory CD8 T cells. Information generated from this aim will provide a practical basis to select new candidate antigens, from the expressed pool of ~5,000 ORF, for evaluation as subunit vaccines to protect against human malaria. Importantly, despite repeated exposures, sterilizing immunity (defined as prevention of blood-stage parasitemia after sporozoite infection) does not develop in individuals living in malaria endemic areas. Indeed our preliminary data reveal both numerical and functional impairment of memory CD8 T cells generated during malaria infection. In aim 2, we will use our newly developed tool-chest, including TCR-retrogenic mice specific for recently identified Plasmodium antigens, to determine how memory CD8 T cells generated after malaria infection are numerically and functionally impaired. Our long-term goal is to understand the mechanisms underlying protective CD8 T cell immunity to liver- stage Plasmodium infection in order to aid in the rational development of effective vaccines. SA 1. Determine why some, but not all Plasmodium antigens are targets of protective CD8 T cells. SA2. Determine the mechanism(s) by which Plasmodium infection results in compromised memory CD8 T cell populations.