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害。超过33亿人面临暴露的风险，每年报告的疟疾新病例为2.5亿例。针对临床相关的疟原虫感染的血液阶段的免疫学策略已经投入了大量的努力，但到目前为止还没有获得许可的疫苗。在疟原虫血液期感染的啮齿动物模型中，寄生虫特异性的CD4T细胞已被证明是保护所必需的。在人类中，寄生虫特异性CD4T细胞的存在与对严重疾病的抵抗力有关。重要的是，保护性CD4T细胞反应的确切特征(数量、表型、功能属性)在很大程度上仍不清楚。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跟踪小鼠血液感染过程中总的寄生虫特异性CD4T细胞反应，而不需要事先了解寄生虫抗原、MHC限制或抗原表位。[使用这种方法，候选人已经确定约氏疟原虫血液期感染导致应答T细胞上多个抑制受体的持续表达，并且这些细胞表现出细胞因子的产生受损，表明这些T细胞在长期疟疾期间经历了功能衰竭。此外，在已确诊的疟疾小鼠中，通过治疗性阻断至少两个抑制物受体与其配体的功能结合，可以立即控制寄生虫复制并增强寄生虫的清除。最后，候选人已经确定，在血液期疟原虫感染期间，抑制性受体阻断对寄生虫特异性CD4和B细胞/抗体反应都有重大影响。这些新的结果为拟议的研究提供了必要的理论基础，以剖析在已确定的临床疟疾小鼠中，治疗性抑制受体阻断后提高寄生虫清除的细胞和体液基础。]应聘者在免疫学技术和与此应用相关的方法方面有10年以上的经验。K22奖项将提供必要的资源，以推进候选人成功建立由NIH R01资助的独立实验室的目标，以详细研究疟疾特异性CD4T细胞和B细胞/抗体反应的数量和质量特征。总之，通过候选人的新途径和方法，这里详细介绍的研究将提供对抗疟原虫适应性免疫特征的重要洞察，这些特征决定了保护，这些特征将影响目前和未来针对疟疾感染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. )