T cell Inhibitory receptor blockade in chronic blood-stage malaria

慢性血期疟疾中的 T 细胞抑制性受体阻断

基本信息

批准号：
9054060
负责人：
John T Harty
金额：
$ 37.75万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054060
关键词：
Address Africa Africa South of the Sahara Antibodies Antibody Response Antigens Antimalarials Area Artemisinins B-Lymphocytes Beds Blood CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Structures Child Chloroquine Chronic Clinical Clinical Trials Complement Culicidae Data Development Disease Drug Targeting Drug resistance Exhibits Goals Health Human Immune response Immunity Immunology Infection Insecticides Intervention Knowledge Licensing Life Liver Malaria Malaria Vaccines Malaria prevention Mali Morbidity - disease rate Mus Nature Parasite Control Parasite resistance Parasites Pharmacotherapy Phenotype Plasmodium Plasmodium falciparum Plasmodium yoelii Population Principal Investigator Production Published Comment Research Resistance development Scourge Staging Surface T cell response T-Lymphocyte Up-Regulation Vaccination Vaccines Virus Diseases artemisinine base combat cytokine exhaust exhaustion global health inhibitory surface receptor malaria infection mortality mouse model novel novel vaccines prevent programs receptor response transmission process vaccine development vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Malaria, caused by Plasmodium parasites, remains an enormous global health problem. The blood-stage of the Plasmodium lifecycle causes malaria related morbidity and mortality and also results in formation of gametocytes that are required for the mosquito vector to transmit disease. Here, we provide data that CD4 T cells in humans exposed to seasonal Plasmodium falciparum infections in Mali, Africa upregulate a surface receptor, PD-1, that is associated with an "exhausted" phenotype in chronic virus infections. To address the generality and relevance of this finding, we applied a novel surrogate activation marker approach to track the total CD4 and CD8 T cell response in a mouse model of Plasmodium yoelii (Py) chronic blood-stage infection. Strikingly, our results show that Py blood-stage infection results in substantial upregulation of surface inhibitory receptors on responding T cells and that these cells exhibit impaired cytokine production, demonstrating that they have undergone functional exhaustion. Of most relevance, blocking inhibitory receptor interactions in mice with established chronic blood-stage Py infection results in immediate control of parasite replication and accelerated clearance of the parasite. New data show that inhibitory receptor blockade enhances CD4 T cell responses and B cells/antibody responses during blood-stage malaria. These results support our long-term goal to understand how inhibitory receptor blockade impacts host immune responses to control clinical malaria. While development of efficacious vaccines and new anti-malarial drugs that target the parasite remain important approaches, successful completion of our studies may reveal an alternative strategy of manipulating host immunity in an antigen-independent fashion for control of the symptomatic blood-stage of Plasmodium infection. We will address these long-term goals through the following specific aims: Aim 1: Determine the T cell components resulting in accelerated clearance of blood-stage P. yoelii infection during inhibitory receptor blockade. Aim 2: Determine the B cell and antibody components resulting in accelerated clearance of blood-stage P. yoelii infection during inhibitory receptor blockade Aim 3. Determine the cellular and humoral basis whereby inhibitory receptor blockade results in complete clearance of persistent P. chabaudi chabaudi blood-stage infection. Aim 4. Determine if and how inhibitory receptor blockade during chronic blood-stage infection impacts cross- species and cross-stage-specific protective immunity to reinfection.

描述（由申请人提供）：由疟原虫寄生虫引起的疟疾仍然是一个巨大的全球健康问题。疟原虫生命周期的血液阶段会导致疟疾相关的发病率和死亡率，还会导致蚊媒传播疾病所需的配子体形成。在这里，我们提供的数据显示，在非洲马里，暴露于季节性恶性疟原虫感染的人类 CD4 T 细胞上调表面受体 PD-1，该受体与慢性病毒感染中的“疲惫”表型相关。为了解决这一发现的普遍性和相关性，我们应用了一种新的替代激活标记方法来追踪约氏疟原虫 (Py) 慢性血期感染小鼠模型中的总 CD4 和 CD8 T 细胞反应。引人注目的是，我们的结果表明 Py 血液阶段感染导致响应 T 的表面抑制受体大幅上调细胞，并且这些细胞表现出细胞因子产生受损，表明它们已经经历了功能衰竭。最重要的是，阻断已患有慢性血期 Py 感染的小鼠体内的抑制性受体相互作用，可以立即控制寄生虫的复制并加速寄生虫的清除。新数据表明，抑制性受体阻断可增强血期疟疾期间 CD4 T 细胞反应和 B 细胞/抗体反应。这些结果支持我们的长期目标，即了解抑制性受体阻断如何影响宿主免疫反应以控制临床疟疾。虽然开发针对寄生虫的有效疫苗和新型抗疟疾药物仍然是重要方法，但我们的研究的成功完成可能会揭示一种以不依赖于抗原的方式操纵宿主免疫的替代策略，以控制疟原虫感染的症状性血液阶段。我们将通过以下具体目标来实现这些长期目标：目标 1：确定在抑制性受体阻断期间加速清除血液期约氏疟原虫感染的 T 细胞成分。目标 2：确定 B 细胞和抗体成分，导致抑制性受体阻断期间加速清除血液阶段约氏疟原虫感染目标 3：确定抑制性受体阻断导致持久性恰鲍迪疟原虫血液完全清除的细胞和体液基础阶段感染。目标 4. 确定慢性血液阶段感染期间抑制性受体阻断是否以及如何影响跨物种和跨阶段针对再感染的特异性保护性免疫。