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

由疟原虫引起的疟疾是未解决的全球健康负担。虽然杀虫剂 经过处理的床网和抗疟药降低了一些疟疾的发病率和严重程度 地区，> 20亿案件每年仍发生> 40万人死亡，其中大多数发生在Young中 撒哈拉以南非洲的儿童。因此，有效的疫苗仍然是未实现但至关重要的目标 应对疟疾的全球威胁。但是，开发有效和可翻译的疫苗反对 我们对免疫的机制的不完全理解所阻碍了疟疾 可以训练系统以控制疟原虫感染。 我们一直在研究CD8 T细胞对肝阶段（LS）疟疾的免疫力约13年。在此期间 时间，我们研究了针对整个寄生虫免疫的免疫力（RAS和滞后差距），并研究了 表位特异性的促进免疫策略，能够产生对免疫的免疫力 小鼠孢子虫挑战。后者研究的一个主要发现是发生了灭菌的免疫力 当免疫产生循环疟疾特异性记忆CD8 T细胞时（以下称为TCIRCM） 这超出了较大但可确定的频率。我们还显示了大量表位特异性 CD8 T细胞存在于免疫小鼠的肝脏中。相反，我们小组和其他人的研究 表明灭菌RAS免疫产生了相对较小的TCIRCM反应，尽管这些反应 反应在肝脏中富集。这个明显的难题最近通过发现解释了 RAS免疫会产生非常有效的肝CD8 T驻留记忆种群（从这里称为 肝脏TRM）对于在此疫苗接种模型中对免疫进行消毒至关重要。 TRM，占据了许多组织， 在组织特异性免疫中起重要作用。这些发现使疟疾领域充满了关注 新型免疫策略以生成TRM以改善LS疫苗。 虽然肝脏TRM在RAS疫苗中的重要性诱导了对疟原虫的保护 夸大了，尚不清楚TCIRCM在多大程度上有助于防止LS感染。 在这里，在未发表的初步数据中，我们提供了证据表明TCIRCM确实可以提供保护性 使用AS尚未定义的机制来快速募集到LS疟原虫感染的免疫力 肝脏。该提案的长期目标是剖析导致生成和功能的机制 可为疟原虫感染提供有效免疫的记忆CD8 T细胞以告知 人类疫苗的开发。我们将以以下特定目标来解决这些目标： SA 1。确定TCIRC快速募集到肝脏的机制 SA 2。剖析TCIRCM的肝脏阶段保护机制 SA 3。确定TCIRCM是否和如何与TRM合作控制肝脏疟疾