T cell Inhibitory receptor blockade in chronic blood-stage malaria

描述(申请人提供)：疟疾，由疟原虫引起，仍然是一个巨大的全球卫生问题。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，还会导致蚊子传播疾病所需的配子体的形成。在这里，我们提供了在非洲马里暴露于季节性恶性疟原虫感染的人的CD4T细胞上调表面受体PD-1的数据，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跟踪约氏疟原虫(Py)慢性血液期感染小鼠模型中总的CD4和CD8T细胞反应。值得注意的是，我们的结果表明，Py血液期感染导致应答T细胞表面抑制受体显著上调。 这些细胞表现出细胞因子的产生受损，表明它们已经经历了功能衰竭。最重要的是，阻断慢性血液期Py感染小鼠的抑制性受体相互作用可以立即控制寄生虫复制并加速寄生虫的清除。新的数据显示，在血液期疟疾期间，抑制受体阻断增强了CD4T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。虽然针对疟原虫的有效疫苗和新的抗疟疾药物的开发仍然是重要的途径，但成功完成我们的研究可能会揭示一种替代策略，即以非抗原依赖的方式操纵宿主免疫，以控制疟原虫感染的症状血液阶段。我们将通过以下具体目标来解决这些长期目标：目标1：在抑制性受体阻断过程中，确定能加速清除血液期约氏假单胞菌感染的T细胞成分。目的2：确定抑制性受体阻断过程中加速清除约氏肺孢子虫血期感染的B细胞和抗体成分。目的3.确定抑制性受体阻断导致持续的沙包氏假丝酵母菌血期感染完全清除的细胞和体液基础。目的4.确定慢性血液期感染中抑制性受体阻断是否以及如何影响对再感染的跨物种和跨阶段特异性保护性免疫。

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.