Investigating the role of oxygen on Plasmodium multiplication rate

研究氧气对疟原虫增殖率的作用

• 批准号: 10593759
• 负责人: Amy Kristine Bei
• 金额: $ 23.32万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593759
• 关键词: Acute; Affect; Amino Acids; Anti-malarial drug resistance; Antimalarials; Antioxidants; Artemisinins; Atmosphere; Biochemical; Biology; Blood; Bone Marrow; Brain; Cell physiology; Cessation of life; Cysteine; DNA Sequence Alteration; Data; Devices; Disease; Dose; Drug resistance; Environment; Environmental Risk Factor; Equilibrium; Erythrocytes; Etiology; Free Radicals; Gases; Gene Expression; Genes; Genetic Transcription; Glutamine; Glutathione; Glycine; Goals; Growth; Human; Hydrogen Peroxide; In Vitro; Individual; Infection; Investigation; Kidney; Laboratories; Length; Liver; Lung; Macaca mulatta; Malaria; Measures; Microscopy; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; Parasites; Pharmacotherapy; Physiological; Plasma; Plasmodium; Plasmodium falciparum; Plasmodium knowlesi; Predisposition; Production; Pulse Oximetry; Quinolones; Reactive Oxygen Species; Reduced Glutathione; Research; Resistance development; Role; Senegal; Severity of illness; Site; Superoxides; System; Testing; Tissues; Uncertainty; Variant; Work; cell injury; confocal imaging; direct application; drug efficacy; glutathione synthase; in vivo; malaria infection; mortality; multiple omics; nonhuman primate; pathogen; response; small molecule; tissue oxygenation

Plasmodium falciparum (P. falciparum) and Plasmodium knowlesi (P. knowlesi) are protozoan pathogens that cause malaria. Of the five species of Plasmodium that infect humans, P. falciparum and P. knowlesi both involve the sequestration of parasitized red blood cells in the deep tissue microvasculature and both cause a range of disease severity. The goal of the proposed study is to understand how fluctuations in the oxygen concentration in the microenvironment, which varies across tissue sites in the body, affect the multiplication rate of P. falciparum and P. knowlesi. The findings from this study are significant toward our understanding of antimalarial drug resistance, as some of the most important antimalarial drugs have been shown to work by triggering increased reactive oxygen species (ROS) in the parasite, and in vitro studies of drug-resistant Plasmodium under different oxygen concentrations have shown variable results. While it is well-known that Plasmodium grows best in the laboratory under low oxygen conditions, little is known about the biology of the parasite under higher oxygen conditions. Our preliminary in vitro data suggests that P. falciparum replicates significantly slower at 13% oxygen (mimicking the oxygen concentration in lungs and liver) versus 1% oxygen (mimicking the oxygen concentration in brain and bone marrow). Confocal imaging suggested lower mitochondrial activity in the 13% condition. Here in Aim 1, we will characterize the cellular and molecular mechanism(s) underlying the variability in multiplication rate under different oxygen conditions, studying this phenomenon in diverse species and strains of Plasmodium. We hypothesize that as oxygen in the microenvironment increases, an increase in intracellular ROS and cellular damage follows, leading to a decline in multiplication rate. In Aim 2, we will directly test whether the parasite’s redox balance affects Plasmodium multiplication rate, through manipulation of ROS and P. falciparum’s glutathione antioxidant system. While much focus exists on characterizing genetic mutations underlying drug resistance, very little work explores the host environmental factors that may also play a role in the redox balance of the parasites, which may in turn contribute to antimalarial drug efficacy in vivo.

恶性疟原虫（P. falciparum）和诺氏疟原虫（P. Knowlesi）是原生动物病原体， 引起疟疾。在感染人类的​​五种疟原虫中，恶性疟原虫和诺氏疟原虫都涉及 寄生红细胞在深层组织微血管中的隔离，两者都会导致一系列 疾病的严重程度。拟议研究的目的是了解氧气浓度的波动如何 体内不同组织部位的微环境各不相同，影响着疟原虫的增殖率。 恶性疟原虫和诺氏疟原虫。这项研究的结果对于我们了解抗疟药具有重要意义 耐药性，因为一些最重要的抗疟药已被证明通过触发而发挥作用 寄生虫中活性氧（ROS）增加，以及耐药疟原虫的体外研究 不同的氧气浓度显示出不同的结果。众所周知，疟原虫生长得最好 在低氧条件下的实验室中，人们对高氧条件下寄生虫的生物学知之甚少。 氧气条件。我们的初步体外数据表明，恶性疟原虫的复制速度显着减慢 13% 氧气（模拟肺和肝脏中的氧气浓度）与 1% 氧气（模拟氧气浓度） 脑和骨髓中的浓度）。共焦成像显示 13% 的线粒体活性较低 健康）状况。在目标 1 中，我们将描述变异性背后的细胞和分子机制 在不同氧气条件下的增殖率，研究不同物种和菌株中的这种现象 疟原虫。我们假设，随着微环境中氧气的增加，细胞内 ROS 和细胞损伤随之而来，导致增殖率下降。在目标 2 中，我们将直接测试是否 通过操纵 ROS 和 P，寄生虫的氧化还原平衡会影响疟原虫的增殖率。 恶性疟原虫的谷胱甘肽抗氧化系统。虽然人们非常关注基因突变的特征 潜在的耐药性，很少有工作探索可能也在其中发挥作用的宿主环境因素 寄生虫的氧化还原平衡，这可能反过来有助于体内抗疟药物的功效。