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

• 批准号: 8369810
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369810
• 关键词: Address; Africa; Africa South of the Sahara; Antibodies; Antibody Formation; 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 Delivery Systems; 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; Pharmaceutical Preparations; 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; mortality; mouse model; novel; novel vaccines; prevent; programs; receptor; response; transmission process; vaccine development; vector mosquito

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. PUBLIC HEALTH RELEVANCE: Plasmodium infections cause 300-500 million cases of malaria each year and have a devastating impact on global human health, with particularly high mortality in children living in sub-Saharan Africa. The lack of vaccines and development of drug resistant parasite strains pose major challenges to prevention of malaria. The goal of the current proposal is to evaluate the potential of T cell inhibitory receptor blockade as an approach to control blood-stage malaria infection that does not rely on vaccination and is not complicated by drug resistant parasites.

描述（由申请人提供）：由疟原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导致疟疾相关的发病率和死亡率，也导致蚊子媒介传播疾病所需的配子体的形成。在这里，我们提供的数据表明，在非洲马里暴露于季节性恶性疟原虫感染的人体内的CD4 T细胞上调了一种表面受体PD-1，这与慢性病毒感染中的“耗尽”表型有关。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跟踪约氏疟原虫（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，我们的研究结果表明，Py血期感染导致表面抑制受体对T的反应大幅上调