Evaluating the role of P53 pathways in malaria

项目总结/摘要 由疟原虫寄生虫引起的疟疾仍然是全球健康威胁，影响约2亿人， 导致每年超过40万人死亡。了解导致病理性 疟疾期间的炎症可以为开发预防性治疗提供见解， 疾病严重程度和死亡率。在儿童每年多次感染疟疾的传播环境中， 在早期寄生虫血症期间钝化炎症可以减轻疾病的严重程度，同时适应性免疫力增加 来控制寄生虫的复制同样，定义宿主过程可以减少肝脏阶段的寄生虫， 当寄生虫负担处于最低水平时，可能会导致预防感染的战略。我们之前已经证明， 未感染的儿童血液中p53和p53靶点的表达增加， 无症状的恶性疟原虫寄生虫血症与后来出现发热性疟疾的儿童有关。 增加p53抑制了P刺激的人单核细胞中炎性细胞因子的产生。 恶性疟原虫，这表明p53在调节疟疾诱导的炎症中起作用。此前， 在小鼠疟疾模型中，提高p53水平可以减少肝脏阶段的寄生虫负担。因此，系统 宿主p53的增加也可能通过抑制肝细胞增殖而使宿主受益，并且巧合的是使已建立的寄生虫受益。 其他疟原虫寄生虫的阶段性重复感染。这项提案的目标是确定宿主途径 适合于治疗干预，这将降低疟疾疾病的严重程度和/或防止肝脏阶段 疟原虫感染。使用两项体外研究，使用来自疟疾暴露人群的人血液样本， 个体和小鼠模型，我们建议确定驱动p53激活的机制， 疟疾暴露儿童先天免疫细胞中的相关途径。我们还将调查系统性 p53激活不仅在免疫细胞中而且在宿主组织中，即肝脏和血管内皮中， 因为它与疟原虫感染和疟疾发病机制有关。我们假设慢性炎症 疟疾反复发作，经常发生在撒哈拉以南非洲的儿童中， 寄生虫血症激活p53及其下游途径系统地调节宿主对 当前和随后的疟原虫感染。为了验证这一假设，我们建议：1）调查的效果 疟原虫感染对先天免疫细胞中p53及其下游通路的影响及其随后的 2）研究疟原虫血液期感染对p53的影响， p53下游通路在宿主肝脏中的作用，并确定p53在调节肝脏分期中的潜在作用 评价p53和p53靶点在感染过程中调节宿主血管内皮的作用。 疟原虫血液期感染。完成这些拟议的目标将提供机械的洞察力， p53在调节疟疾诱导的发病机制和肝脏阶段感染中的作用， 旨在减轻疟疾疾病严重程度和/或肝脏阶段预防的干预措施目标。

Project Summary/Abstract Malaria caused by the Plasmodium parasite remains a global health threat, affecting ~200 million people and leading to more than 400,000 deaths per year. Understanding the mechanisms contributing to pathological inflammation during malaria can provide insight for the development of adjunctive therapies that can reduce disease severity and mortality. In transmission settings where children suffer multiple malaria episodes per year, blunting inflammation during early parasitemia can mitigate disease severity while adaptive immunity ramps up to control parasite replication. Likewise, defining host processes that can reduce parasites during the liver stage, when parasite burden is at its lowest, may lead to strategies to prevent infection. We have previously shown that expression of p53 and p53 targets were increased in the blood of uninfected children who would later present with asymptomatic P. falciparum parasitemia relative to children who later presented with febrile malaria. Increasing p53 dampened the production of inflammatory cytokines in human monocytes stimulated with P. falciparum, suggesting that p53 plays a role in modulating malaria-induced inflammation. It was also previously shown that boosting p53 levels can reduce liver-stage parasite burden in a mouse malaria model. Thus, systemic increases in host p53 may also benefit the host, and coincidently the established parasite, by inhibiting liver- stage superinfection by other Plasmodium parasites. The goal of this proposal is to identify host pathways amenable to therapeutic intervention that would either reduce malaria disease severity and/or prevent liver-stage infection by Plasmodium parasites. Using both in vitro studies with human blood samples from malaria-exposed individuals and mouse models, we propose to determine the mechanisms that drive the activation of p53 and associated pathways in innate immune cells of malaria-exposed children. We will also investigate the systemic effects of p53 activation in not only immune cells but also host tissue, namely the liver and vascular endothelium, as it relates to Plasmodium infection and malaria pathogenesis. We hypothesize that chronic inflammation induced by repeated malaria episodes, which frequently occurs in sub-Saharan African children, or chronic parasitemia activates p53 and its downstream pathways systemically to modulate the host response to both the current and subsequent Plasmodium infections. To test this hypothesis, we propose to: 1) investigate the effect of Plasmodium infection on p53 and its downstream pathways in innate immune cells and their subsequent response to repeat malaria exposure; 2) investigate the effect of Plasmodium blood-stage infection on p53 and p53 downstream pathways within the host liver and determine the potential role for p53 in modulating liver-stage superinfection; and 3) evaluate the role of p53 and p53 targets in regulating host vascular endothelium during Plasmodium blood-stage infection. Completion of these proposed aims will provide mechanistic insight into the role of p53 in modulating malaria-induced pathogenesis and liver-stage infection, which may identify druggable targets for interventions aimed at mitigating malaria disease severity and/or liver-stage prophylaxis.