Memory CD8 T cell immunity to Plasmodium liver stage infec

 描述(申请人提供)：疟疾，由疟原虫引起，仍然是一个尚未解决的全球健康负担，影响着世界40%的人口。尽管驱虫蚊帐和抗疟疾药物的供应减少了一些区域的疟疾发病率和严重程度，但每年仍有约2亿例疟疾病例，2013年约有85万人死亡。因此，预防疟疾的疫苗仍然是对抗这一全球威胁的一个尚未实现但至关重要的目标。我们的初步数据显示，只有部分能引起CD8T细胞反应的疟原虫抗原是CD8T细胞介导的不孕免疫的靶标。目标1将阐述确定特定疟原虫抗原是否是记忆CD8 T细胞有效保护的目标的机制。这一目的产生的信息将为从~5,000个ORF表达池中选择新的候选抗原提供实用基础，以作为亚单位疫苗进行评估，以预防人类疟疾。重要的是，尽管反复暴露，但在疟疾流行地区生活的个人中，灭菌免疫(定义为预防子孢子感染后的血期寄生虫病)并未形成。事实上，我们的初步数据显示，在疟疾感染期间产生的记忆CD8 T细胞在数量和功能上都受到了损害。在目标2中，我们将使用我们新开发的工具箱，包括针对最近发现的疟原虫抗原的TCR逆转录基因小鼠，以确定疟疾感染后产生的记忆CD8 T细胞在数量和功能上是如何受损的。我们的长期目标是了解CD8 T细胞对肝期疟原虫感染的保护性免疫机制，以帮助合理开发有效的疫苗。确定为什么某些而不是所有的疟原虫抗原是保护性CD8 T细胞的靶标。SA2.确定疟原虫感染导致记忆性CD8T细胞群受损的机制(S)。

 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.