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一个尚未解决的全球健康负担。虽然有杀虫剂 经过处理的蚊帐和抗疟药物降低了一些国家疟疾的发病率和严重程度 地区，每年仍发生超过 2 亿例病例，死亡人数超过 40 万人，其中大多数发生在年轻人 撒哈拉以南非洲地区的儿童。因此，有效的疫苗仍然是一个尚未实现但至关重要的目标 对抗疟疾的全球威胁。然而，有效且可转化的疫苗的开发 由于我们对免疫机制的不完全了解，疟疾的防治一直受到阻碍。 可以训练系统来控制疟原虫感染。 我们研究 CD8 T 细胞对肝期 (LS) 疟疾的免疫已有约 13 年的时间。在此期间 当时，我们研究了针对整个寄生虫免疫（RAS 和晚期逮捕 GAP）的免疫力，并研究了 表位特异性初免-加强免疫策略，能够产生灭菌免疫 小鼠子孢子挑战。后者研究的一个主要发现是，杀菌免疫发生了 当免疫产生循环疟疾特异性记忆 CD8 T 细胞（本文称为 Tcircm）时 超过了一个很大但可定义的频率。我们还表明大量的表位特异性 CD8 T 细胞存在于免疫小鼠的肝脏中。相比之下，我们小组和其他人的研究 结果表明，灭菌 RAS 免疫产生相对较小的 Tcircm 反应，尽管这些 反应在肝脏中丰富。最近的发现解释了这个明显的难题 RAS 免疫产生了非常有效的肝脏 CD8 T 常驻记忆群体（从这里开始，称为 肝 Trm），对于该疫苗接种模型中的免疫灭菌至关重要。 Trm，占据许多组织并且 在组织特异性免疫中发挥重要作用。这些发现促使疟疾领域关注 产生 Trm 来改进 LS 疫苗的新免疫策略。 虽然肝脏 Trm 在 RAS 疫苗诱导的疟原虫保护中的重要性尚不能确定。 虽然言过其实，但目前尚不清楚 Tcircm 在多大程度上（如果有的话）有助于预防 LS 感染。 在这里，在未发表的初步数据中，我们提供了 Tcircm 确实可以提供保护性的证据 使用尚未明确的机制快速招募以抵抗 LS 疟原虫感染 肝脏。该提案的长期目标是剖析导致生成和功能的机制 记忆 CD8 T 细胞可以对疟原虫 LS 感染提供强大的免疫力，以便告知 人类疫苗的开发。我们将通过以下具体目标来实现这些目标： SA 1. 确定 Tcircm 快速募集至肝脏的机制 SA 2.剖析Tcircm的肝阶段保护机制 SA 3. 确定 Tcircm 是否以及如何与 Trm 合作控制肝期疟疾