Effector and regulatory T cell responses and protection from clinical malaria

描述(申请人提供)：每年，疟疾夺走了100多万人的生命，其中大部分是幼儿。迫切需要一种有效的疟疾疫苗，但由于我们对疟疾自然免疫机制的了解有限，以及缺乏可靠的体外保护相关因素，阻碍了实现这一目标的进展。来自人类和动物实验的数据提供了希望，即疫苗介导的对疟疾的免疫诱导是可以实现的。感染受辐射的子孢子，在肝脏阶段阻止发育，在人类中提供无菌保护性免疫，表明T细胞对红细胞前抗原的反应起着重要作用。重要的是，在小鼠和最近的人类身上进行的研究表明，在氯喹的掩护下给予未减毒的寄生虫也能产生类似的保护作用，氯喹可以预防血液期疟疾，但不会影响肝脏阶段。总而言之，这些数据表明，限制暴露于血液期感染实际上可能通过避免寄生虫血症诱导的免疫抑制机制，实际上增强对红细胞前期阶段的免疫反应。这项拟议的研究将利用收集的样本，作为设在乌干达托罗罗的随机临床试验的一部分，该试验将比较3种有希望的疟疾化学预防策略的有效性和安全性，与目前不进行化学预防的标准进行比较。这项试验提供了一个独特的机会来研究化学预防对处于高传播环境中的婴儿对自然感染的疟疾特异性免疫反应的影响。我们将验证这样的假设，即通过化学预防选择性地抑制红细胞期疟疾将促进针对红细胞前抗原的高功能T细胞反应的发展，并限制免疫抑制机制的诱导，从而促进保护性抗疟疾免疫的发展。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。针对红细胞期和红细胞期恶性疟原虫抗原的CD4和CD8T细胞的频率、广度和功能属性将在随机接受化学预防和不接受干预的儿童之间进行纵向比较。在第二个目标中，我们将评估反复寄生虫血症对免疫抑制机制和T细胞功能障碍发展的影响。我们假设，免疫调节机制，包括Foxp3调节的CD4T细胞，是由寄生虫血症诱导的，并干扰建立有效的、持久的疟疾特异性T细胞反应，这是保护性免疫所必需的。在第三个目标中，我们将根据暴露的流行病学协变量进行调整，确定疟疾特异性T细胞反应和/或免疫抑制机制是否与停止化学预防后对疟疾的预期保护有关。这些研究将极大地提高我们对疟疾在婴儿期获得自然免疫力的理解。 公共卫生意义：疟疾是全世界儿童的头号杀手，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。我们将对参加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，这些免疫参数将与停止化学预防后对临床疟疾的预期保护相关。化学预防可预防血液期疟疾，但不能预防肝期疟疾。

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