Immunity to Liver-stage malaria

对肝期疟疾的免疫力

• 批准号: 10411766
• 负责人: John T Harty
• 金额: $ 56.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411766
• 关键词: Address; Africa South of the Sahara; Antibodies; Antigens; Antimalarials; Attenuated; Beds; Bite; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Child; Clinical; Culicidae; Data; Dermal; Development; Drug resistance; Epitopes; Erythrocytes; Frequencies; Generations; Goals; Hepatocyte; Human; Immune system; Immunity; Immunization; Immunize; Immunology; Incidence; Infection; Insecticides; Invaded; Knowledge; Laboratories; Liver; Malaria; Malaria Vaccines; Mediating; Membrane; Memory; Modeling; Mus; Parasites; Pharmacotherapy; Plasmodium; Play; Population; Property; Radiation; Research; Rodent; Rodent Model; Role; Route; Severities; Sporozoite vaccine; Sporozoites; T-Lymphocyte; Time; Tissues; Training; United States National Institutes of Health; Vaccination; Vaccines; combat; disease transmission; global health; improved; malaria transmission; novel; prevent; recruit; response; vaccination strategy; vaccine development; vaccine-induced immunity

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

疟疾是由疟原虫引起的，是一个尚未解决的全球健康负担。虽然杀虫剂 经过处理的蚊帐和抗疟疾药物降低了一些国家的疟疾发病率和严重程度。 各地区每年仍有200,000,000例死亡，其中大部分发生在年轻人。 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，有效的和可翻译的疫苗的开发 疟疾一直受到我们对免疫机制的不完全理解的阻碍 可以对系统进行培训以控制疟原虫感染。 近13年来，我们一直在研究CD8 T细胞对肝期(LS)疟疾的免疫。在此期间 时间，我们研究了对整个寄生虫免疫(RAS和迟捕GAP)的免疫力，并研究了 能够产生灭菌免疫的表位特异性原基增强免疫策略 小鼠子孢子的挑战。后一项研究的一个主要发现是出现了不孕免疫。 当免疫产生循环中的疟疾特异性记忆CD8T细胞(以下称为TCircm) 这超过了一个很大但可定义的频率。我们还发现了大量的表位特异性 免疫小鼠肝脏中可见CD8T细胞。相比之下，我们小组和其他人的研究 显示灭菌RAS免疫产生相对较小的TCircm反应，尽管这些 这些反应在肝脏中得到了丰富。这一明显的难题最近被这一发现解释了 RAS免疫会产生非常强大的肝脏CD8 T驻留记忆群体(从这里起，称为 在该疫苗接种模式中，这是灭菌免疫所必需的。TRM，占据了许多纸巾和 在组织特异性免疫中发挥重要作用。这些发现激发了疟疾领域的关注 产生Trm以改进LS疫苗的新免疫策略。 虽然肝trm在RAS疫苗诱导的抗疟原虫保护中的重要性不能 夸大了这一点，目前还不清楚TCircm对LS感染的保护作用有多大，如果有的话。 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 利用一种尚未确定的快速募集机制免疫LS疟原虫感染 肝脏。这项提议的长期目标是剖析导致产生和功能的机制 能对疟原虫LS感染提供强大免疫力的记忆CD8 T细胞 人类疫苗的开发。我们将通过以下具体目标实现这些目标： 确定TCircm快速募集到肝脏的机制 SA 2.剖析TCircm对肝期保护的作用机制 SA 3.确定TCircm是否以及如何与Trm合作控制肝期疟疾