T cell Inhibitory receptor blockade in chronic blood-stage malaria

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导致疟疾相关的发病率和死亡率，并且还导致蚊子媒介传播疾病所需的配子母细胞的形成。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类中，CD 4 T细胞上调了一种表面受体PD-1，该受体与慢性病毒感染中的“衰竭”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物方法来跟踪约氏疟原虫（Py）慢性血液期感染小鼠模型中的总CD 4和CD 8 T细胞应答。引人注目的是，我们的研究结果表明，Py血液阶段感染导致T细胞表面抑制性受体的大量上调， 细胞，并且这些细胞表现出受损的细胞因子产生，表明它们已经经历了功能衰竭。最相关的是，在具有已建立的慢性血液阶段Py感染的小鼠中阻断抑制性受体相互作用导致寄生虫复制的立即控制和寄生虫的加速清除。新的数据表明，抑制性受体阻断增强血液期疟疾期间的CD 4 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，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。虽然开发针对疟原虫的有效疫苗和新的抗疟疾药物仍然是重要的方法，但我们的研究的成功完成可能揭示了以抗原非依赖性方式操纵宿主免疫以控制疟原虫感染的症状性血液阶段的替代策略。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导致血液阶段约氏疟原虫感染加速清除的T细胞组分。目标二：确定在抑制性受体阻断期间导致血液期约氏疟原虫感染加速清除的B细胞和抗体组分目的3。确定细胞和体液基础，从而抑制性受体阻断导致持续性夏氏疟原虫血液期感染的完全清除。目标4。确定在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特异性保护性免疫以防止再感染。

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.