Effector and regulatory T cell responses and protection from clinical malaria

描述（由申请人提供）：每年，疟疾夺去100多万人的生命，其中大多数是幼儿。迫切需要一种有效的疟疾疫苗，但由于我们对疟疾天然免疫机制的了解有限，以及缺乏可靠的体外保护相关物，这一目标的进展受到阻碍。来自人类和动物实验的数据提供了希望，即疫苗介导的疟疾免疫诱导是可以实现的。在肝脏阶段，受辐照子孢子的感染可阻止发育，在人体内产生无菌保护性免疫，这表明T细胞对红细胞前抗原的应答具有重要作用。重要的是，对小鼠和最近对人类的研究表明，在氯喹的掩护下给予非减毒寄生虫时，也能提供类似的保护，氯喹可预防血液期疟疾，但不影响肝脏期。总之，这些数据表明，限制暴露于血液阶段感染实际上可能会增强免疫反应的红细胞前期阶段的发展，也许是通过避免寄生虫血症诱导的免疫抑制机制。这项拟议的研究将利用作为乌干达托罗罗随机临床试验的一部分收集的样本，该试验将比较3种有希望的疟疾化学预防策略与目前无化学预防的标准的有效性和安全性。这项试验提供了一个独特的机会来研究化学预防的影响，它将肝脏阶段和血液阶段的疟疾分开，对高传播环境中婴儿对自然感染的疟疾特异性免疫反应的影响。我们将测试这一假设，即通过化学预防选择性抑制红细胞期疟疾将增强靶向红细胞前抗原的高功能性T细胞应答的发展，并限制免疫抑制机制的诱导，从而促进保护性抗疟免疫的发展。在第一个目标中，我们将前瞻性地评估有效的化学预防对婴儿期恶性疟原虫适应性T细胞反应的发展的影响。将在随机接受化学预防与无干预的儿童之间纵向比较靶向红细胞前期和红细胞期恶性疟原虫抗原的CD 4和CD 8 T细胞的频率、广度和功能属性。在第二个目标中，我们将评估复发性寄生虫血症对免疫抑制机制和T细胞功能障碍的影响。我们假设免疫调节机制，包括Foxp 3+调节性CD 4 T细胞，是由寄生虫血症诱导的，并干扰保护性免疫所必需的有效，持久的疟疾特异性T细胞应答的建立。在第三个目标中，我们将确定是否疟疾特异性T细胞反应和/或免疫抑制机制与疟疾的前瞻性保护停止化学预防后，调整暴露的流行病学协变量。这些研究将大大提高我们对婴儿期获得疟疾天然免疫力的认识。 公共卫生相关性：疟疾是全世界儿童的主要杀手，但由于我们对疟疾寄生虫感染的免疫反应缺乏了解，开发预防性疫苗的努力失败了。我们将对参与化学预防策略临床试验的乌干达婴儿对疟疾的免疫反应进行详细的纵向研究。接受化学预防的儿童的免疫反应将与未接受化学预防的儿童进行比较，化学预防可预防血液期疟疾，但不能预防肝脏期疟疾，这些免疫参数将与停止化学预防后预防临床疟疾的预期保护相关联

DESCRIPTION (provided by applicant): Each year, malaria claims the lives of over a million individuals, mostly young children. An effective malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying natural immunity to malaria and a lack of reliable in vitro correlates of protection. Data from both human and animal experiments offer hope that vaccine-mediated induction of immunity to malaria is achievable. Infection with irradiated sporozoites, which arrest development during the liver stage, confers sterile protective immunity in humans, suggesting an important role for the T cell response to pre-erythrocytic antigens. Importantly, studies in mice and more recently in humans demonstrate that similar protection is conferred by non-attenuated parasites when given under cover of chloroquine, which prevents blood stage malaria but does not impact the liver stage. Together these data indicate that limiting exposure to blood stage infection may actually enhance the development of immune responses to pre-erythrocytic stages, perhaps by avoiding the immunosuppressive mechanisms induced by parasitemia. The proposed study will leverage samples to be collected as part of a randomized clinical trial based in Tororo, Uganda that will compare the efficacy and safety of 3 promising malaria chemopreventive strategies with the current standard of no chemoprevention. This trial provides a unique opportunity to study the impact of chemoprevention, which uncouples liver-stage and blood-stage malaria, on the malaria-specific immune response to natural infection among infants in a high transmission setting. We will test the hypothesis that selective suppression of erythrocytic stage malaria by chemoprevention will enhance the development of highly functional T cell responses targeting pre-erythrocytic antigens and limit the induction of immunosuppressive mechanisms, and will thus foster the development of protective antimalarial immunity. In the first aim, we will prospectively evaluate the impact of potent chemoprevention on the development of the adaptive T cell response to P. falciparum during infancy. The frequency, breadth, and functional attributes of CD4 and CD8 T cells targeting pre-erythrocytic and erythrocytic stage P. falciparum antigens will be compared longitudinally between children randomized to receive chemoprevention vs. no intervention. In the second aim, we will assess the impact of recurrent parasitemia on the development of immune suppressor mechanisms and T cell dysfunction. We hypothesize that immune regulatory mechanisms, including Foxp3+ regulatory CD4 T cells, are induced by parasitemia and interfere with the establishment of effective, durable malaria-specific T cell responses that are necessary for protective immunity. In the third aim, we will determine whether malaria-specific T cell responses and/or immune suppressor mechanisms are associated with prospective protection from malaria following cessation of chemoprevention, following adjustment for epidemiologic covariates of exposure. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria in infancy. PUBLIC HEALTH RELEVANCE: Malaria is a leading killer of children worldwide, but efforts to develop a preventive vaccine have failed due to our poor understanding of the immune response to infection by malaria parasites. We will perform detailed longitudinal studies of the immune response to malaria in Ugandan infants participating in a clinical trial of chemoprevention strategies. The immune responses of children receiving chemoprevention, which prevents blood-stage but not liver-stage malaria, will be compared to children who do not receive chemoprevention, and these immune parameters will be correlated with prospective protection from clinical malaria following cessation of chemoprevention