Immunity to Liver-stage malaria

由疟原虫引起的疟疾是一个尚未解决的全球健康负担。虽然杀虫剂 驱虫蚊帐和抗疟药物减少了一些国家的疟疾发病率和严重程度， 在一些地区，每年仍有超过200，000，000例病例发生，死亡人数超过400，000人，其中大多数发生在年轻人中， 撒哈拉以南非洲的儿童。因此，有效的疫苗仍然是一个尚未实现但关键的目标， 抗击疟疾的全球威胁。然而，开发有效的和可翻译的疫苗， 我们对免疫机制的不完全理解阻碍了疟疾的发展， 可以训练系统来控制疟原虫感染。 我们一直在研究CD 8 T细胞免疫肝期（LS）疟疾~13年。在此 同时，我们研究了对整个寄生虫免疫（RAS和晚捕GAP）的免疫力，并研究了 表位特异性初免-加强免疫策略，能够产生对 小鼠子孢子攻击。后一项研究的主要发现是， 当免疫产生循环的疟疾特异性记忆CD 8 T细胞（以下称为Tcircm）时， 超过了一个很大但可以定义的频率我们还发现，大量的表位特异性 免疫小鼠肝脏中存在CD 8 T细胞。相反，我们小组和其他人的研究 表明灭活RAS免疫产生相对较小的Tcircm应答，尽管这些 反应在肝脏中富集。最近的发现解释了这个明显的难题 RAS免疫产生了一个非常有效的肝脏CD 8 T驻留记忆群体（从这里，称为 肝Trm），其对于在该疫苗接种模型中消除免疫力是必需的。占据许多组织， 在组织特异性免疫中起重要作用。这些发现激发了疟疾领域关注 新的免疫策略产生Trm以改进LS疫苗。 虽然不能确定肝脏Trm在RAS疫苗诱导的抗疟原虫保护中的重要性， 虽然言过其实，但仍不清楚Tcircm在多大程度上（如果有的话）有助于保护免受LS感染。 在这里，在未发表的初步数据中，我们提供了Tcircm确实可以提供保护的证据。 使用尚未确定的快速募集机制对LS疟原虫感染产生免疫力， 肝脏这项提案的长期目标是剖析导致产生和发挥作用的机制 记忆性CD 8 T细胞可以提供对疟原虫LS感染的有效免疫， 人类疫苗的发展。我们将通过以下具体目标实现这些目标： SA 1.确定Tcircm快速募集至肝脏的潜在机制 SA 2. Tcircm肝期保护机制的研究 SA 3.确定Tcircm是否以及如何与Trm合作控制肝期疟疾

Malaria, caused by Plasmodium species, is an unresolved global health burden. Although insecticide treated bed nets and antimalarial drugs have reduced the incidence and severity of malaria in some regions, >200,000,000 cases still occur annually with >400,000 fatalities, most of which occur in young children in sub-Saharan Africa. Thus, effective vaccines remain an as yet unrealized but critical goal to combat the global threat of malaria. However, development of potent and translatable vaccines against malaria has been hampered by our incomplete understanding of the mechanisms by which the immune system can be trained to control Plasmodium infections. We have been studying CD8 T cell immunity to liver-stage (LS) malaria for ~13 years. During this time, we studied immunity against whole parasite immunizations (RAS and late-arresting GAP) and studied epitope-specific prime-boost immunization strategies that were capable of generating sterilizing immunity to sporozoite challenge in mice. A major finding from the latter studies was that sterilizing immunity occurred when the immunization generated circulating malaria-specific memory CD8 T cells (hereon called Tcircm) that exceeded a large, but definable frequency. We also showed that large numbers of epitope-specific CD8 T cells were present in the livers of immunized mice. In contrast, studies from our group and others showed that sterilizing RAS immunization generated relatively small Tcircm responses, although these responses were enriched in the liver. This apparent conundrum was recently explained by the discovery that RAS immunization generates a very potent liver CD8 T resident memory population (from here, called liver Trm) that is essential for sterilizing immunity in this vaccination model. Trm, occupy many tissues and play important roles in tissue specific immunity. These findings have galvanized the malaria field to focus on novel immunization strategies to generate Trm to improve LS vaccines. While the importance of liver Trm in RAS vaccine induced protection from Plasmodium cannot be overstated, it remains unclear to what degree, if any, Tcircm contribute to protection against LS infection. Here, in unpublished preliminary data, we provide evidence that Tcircm can indeed provide protective immunity against LS Plasmodium infection using an as yet undefined mechanism for rapid recruitment to the liver. The long-term goals of this proposal are to dissect mechanisms leading to generation and function of memory CD8 T cells that can provide potent immunity to Plasmodium LS infection in order to inform development of human vaccines. We will address these goals with the following Specific Aims: SA 1. Determine the mechanisms underlying rapid recruitment of Tcircm to the liver SA 2. Dissect the mechanisms of liver-stage protection by Tcircm SA 3. Determine if and how Tcircm cooperate with Trm in control of liver-stage malaria