Evaluating the role of P53 pathways in malaria

项目摘要/摘要 由疟原虫引起的疟疾仍然是一个全球健康威胁，影响到约2亿人和 每年导致40多万人死亡。了解导致病理改变的机制 疟疾期间的炎症可以为开发辅助疗法提供洞察力，这些辅助疗法可以减少 疾病严重程度和死亡率。在儿童每年遭受多次疟疾发作的传播环境中， 在寄生虫血症早期钝化炎症可以减轻疾病严重性，同时增强获得性免疫 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， 当寄生虫负担最低时，可能会导致采取预防感染的策略。我们之前已经表明， 未感染的儿童血液中P53和P53靶蛋白的表达增加，这些儿童后来出现 与后来出现发热疟疾的儿童相比，有无症状的恶性疟原虫寄生虫病。 P53蛋白的升高抑制了P。 恶性疟原虫，表明P53在调节疟疾引起的炎症中发挥作用。它以前也是 研究表明，在小鼠疟疾模型中，提高p53水平可以减少肝期寄生虫的负担。因此，系统性的 宿主P53的增加也可能有利于宿主，巧合的是，通过抑制肝脏- 被其他疟原虫重叠感染。该提案的目标是确定宿主路径 易于接受治疗干预，以减轻疟疾的严重程度和/或防止肝期 被疟原虫感染。对接触疟疾的人的血液样本进行这两项体外研究 个体和小鼠模型，我们建议确定驱动P53和P53激活的机制 暴露于疟疾的儿童先天免疫细胞中的相关途径。我们还将调查系统性的 P53的激活不仅在免疫细胞中，而且在宿主组织中，即肝脏和血管内皮细胞， 因为它与疟原虫感染和疟疾的发病机制有关。我们假设慢性炎症 由反复发作的疟疾引起的，这种情况经常发生在撒哈拉以南非洲的儿童中，或慢性 寄生虫血症系统地激活P53及其下游通路，调节宿主对这两种蛋白的反应 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 疟原虫感染对先天免疫细胞中P53及其下游途径的影响 对疟疾反复暴露的反应；2)研究疟原虫血期感染对P53和P53的影响 P53在宿主肝脏中的下游途径并确定P53在调节肝脏分期中的潜在作用 3)评价P53和P53靶点在调节宿主血管内皮细胞中的作用。 疟原虫血液期感染。这些拟议目标的完成将提供对 P53在调控疟疾致病机制和肝期感染中的作用 旨在减轻疟疾疾病严重性和/或肝脏阶段预防的干预措施的目标。

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.