Evaluating the role of P53 pathways in malaria

评估 P53 通路在疟疾中的作用

• 批准号: 10184664
• 负责人: Tuan Manh Tran
• 金额: $ 63.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184664
• 关键词: Address; Adjuvant Therapy; Affect; African; Anopheles Genus; Area; Biological Models; Biology; Bite; Blood; Blood Circulation; Blood specimen; Cells; Cerebral Malaria; Cessation of life; Child; Chronic; Culicidae; Development; Disease; Endothelial Cells; Endothelium; Falciparum Malaria; Fever; Goals; Hepatocyte; Human; Immune; Immune response; In Vitro; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Intervention; Investigation; Lead; Liver; Malaria; Mediating; Modeling; Molecular; Mus; Outcome; Parasite Control; Parasitemia; Parasites; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Plasma; Plasmodium; Plasmodium falciparum; Play; Process; Production; Prophylactic treatment; Prospective cohort study; Ramp; Recurrence; Regulation; Role; Sampling; Severity of illness; Signal Pathway; Sporozoites; Stimulus; System; TP53 gene; Testing; Therapeutic Intervention; Tissues; Vascular Endothelium; Work; adaptive immune response; adaptive immunity; base; cytokine; druggable target; global health; humanized mouse; in vitro Model; insight; malaria infection; malaria transmission; monocyte; mortality; mouse model; prevent; response; superinfection; transmission process

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.

项目概要/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 亿人和 每年导致超过 40 万人死亡。了解导致病理的机制 疟疾期间的炎症可以为开发辅助疗法提供见解，从而减少 疾病的严重程度和死亡率。在儿童每年遭受多次疟疾发作的传播环境中， 减弱早期寄生虫血症期间的炎症可以减轻疾病的严重程度，同时适应性免疫增强 来控制寄生虫的复制。同样，定义可以减少肝脏阶段寄生虫的宿主过程， 当寄生虫负担最低时，可能会导致采取预防感染的策略。我们之前已经证明了 未感染儿童的血液中 p53 和 p53 靶标的表达增加，这些儿童随后出现 与后来出现热性疟疾的儿童相关的无症状恶性疟原虫寄生虫血症。 p53 的增加抑制了 P 刺激的人单核细胞中炎症细胞因子的产生。 恶性疟原虫，表明 p53 在调节疟疾引起的炎症中发挥作用。此前也曾 研究表明，提高 p53 水平可以减少小鼠疟疾模型中肝期寄生虫的负担。因此，系统性 宿主 p53 的增加也可能通过抑制肝细胞而使宿主受益，同时也使已建立的寄生虫受益。 其他疟原虫寄生虫的阶段重复感染。该提案的目标是确定宿主途径 适合治疗干预，以降低疟疾疾病的严重程度和/或预防肝期 疟原虫寄生虫感染。使用来自疟疾暴露人群的人体血液样本进行体外研究 个体和小鼠模型，我们建议确定驱动 p53 和 暴露于疟疾的儿童先天免疫细胞的相关途径。我们还将进行系统性的调查 p53 激活不仅影响免疫细胞，还影响宿主组织，即肝脏和血管内皮， 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 由疟疾反复发作引起，这种情况经常发生在撒哈拉以南非洲儿童中，或慢性疟疾 寄生虫血症系统性地激活 p53 及其下游通路，以调节宿主对 当前和随后的疟原虫感染。为了检验这个假设，我们建议：1）调查效果 先天免疫细胞中p53及其下游通路的疟原虫感染及其后续研究 对反复接触疟疾的反应； 2) 研究疟原虫血期感染对p53和p53的影响 p53 在宿主肝脏内的下游通路并确定 p53 在调节肝脏阶段中的潜在作用 重复感染； 3）评估p53和p53靶标在调节宿主血管内皮细胞过程中的作用 疟原虫血期感染。完成这些拟议的目标将为我们提供机制上的见解 p53 在调节疟疾诱发的发病机制和肝期感染中的作用，这可能会识别可药物治疗 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。