Role of CD4 T cell inhibitor receptors during Plasmodium blood stage infection

描述（由申请人提供）：疟原虫感染对人类公共健康造成重大损失。超过33亿人面临暴露风险，每年报告2.5亿新发疟疾病例。许多努力都是针对疟原虫感染的临床相关血液阶段制定免疫策略，但迄今为止还没有获得许可的疫苗。在疟原虫血期感染的啮齿动物模型中，寄生虫特异性CD4 T细胞已被证明是必要的保护。在人类中，寄生虫特异性CD4 T细胞的存在与对严重疾病的抵抗力相关。重要的是，保护性CD4 T细胞反应的确切特征（数量、表型、功能属性）在很大程度上仍然未知。该候选人最近开发并应用了一种新的替代激活标记方法来追踪小鼠疟原虫血液感染期间寄生虫特异性CD4 T细胞的总反应，而无需先验地了解寄生虫抗原，MHC限制或表位。[使用这种方法，候选人已经确定，约氏疟原虫血期感染导致应答T细胞上多种抑制受体的持续表达，并且这些细胞表现出受损的细胞因子产生，表明这些T细胞在长期疟疾期间经历了功能衰竭。此外，在患有疟疾的小鼠中，通过治疗阻断至少两种抑制剂受体与其配体的功能结合，可立即控制寄生虫复制并增强寄生虫清除。最后，候选人已经确定抑制受体阻断对疟原虫感染期间寄生虫特异性CD4和B细胞/抗体反应有重要影响。这些新结果为提出的研究提供了必要的理论基础，以解剖在临床疟疾小鼠中治疗性抑制受体阻断后增强寄生虫清除的细胞和体液基础。候选人有10年以上与此应用相关的免疫学技术和方法的经验。K22奖将提供必要的资源，以推进候选人成功建立NIH R01资助的独立实验室的目标，以详细研究疟原虫特异性CD4 T细胞和B细胞/抗体反应的定量和定性特征。总的来说，凭借候选人的新方法和方法论，本文详细介绍的研究将为确定保护作用的抗疟原虫适应性免疫的特征提供关键见解，这将影响当前和未来在疟原虫感染背景下的治疗和疫苗设计方法。)

DESCRIPTION (provided by applicant): Plasmodium infection exacts a significant toll on human public health. More than 3.3 billion people are at risk for exposure and >250 million new cases of malaria are reported each year. Much effort has been directed towards developing immunologic strategies that target the clinically relevant blood stage of Plasmodium infection, but to date no licensed vaccines exist. In rodent models of Plasmodium blood stage infection, parasite-specific CD4 T cells have been shown to be necessary for protection. In humans, the presence of parasite-specific CD4 T cells correlates with resistance to severe disease. Importantly, the precise characteristics of protective CD4 T cell responses (numbers, phenotype, functional attributes) remain largely unknown. The candidate has recently developed and applied a novel surrogate activation marker approach to track the total, parasite-specific CD4 T cell response during Plasmodium blood infection in mice, without a priori knowledge of parasite antigens, MHC restriction or epitopes. [Using this approach, the candidate has determined that Plasmodium yoelii blood stage infection results in sustained expression of multiple inhibitory receptors on responding T cells and that these cells exhibit impaired cytokine production, demonstrating that these T cells have undergone functional exhaustion during prolonged malaria. Moreover, therapeutically blocking the functional engagement of at least two inhibitor receptors with their ligands in mice with established malaria results in immediate contro of parasite replication and enhanced parasite clearance. Finally, the candidate has determined that inhibitory receptor blockade has major impacts on both parasite-specific CD4 and B cell/antibody responses during blood stage Plasmodium infection. These new results provide the necessary rationale for the proposed studies to dissect the cellular and humoral basis for enhanced parasite clearance following therapeutic inhibitory receptor blockade in mice with established clinical malaria.] The candidate has more than 10 years of experience with immunologic techniques and approaches relevant to this application. The K22 award will provide the resources necessary to advance the candidate's goal of successfully establishing an NIH R01- funded, independent laboratory to study in detail the quantitative and qualitative features of Plasmodium- specific CD4 T cell and B cell/antibody responses. Collectively, by virtue of the candidate's new approaches and methodologies, the studies detailed herein will provide critical insight into the features of anti-Plasmodial adaptive immunity that determine protection, which will impact current and future therapies and approaches to vaccine design in the context of Plasmodium infection. )