Investigating the role of oxygen on Plasmodium multiplication rate

恶性疟原虫(恶性疟原虫)和诺氏疟原虫(诺氏疟原虫)是原生动物病原体 导致疟疾。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 寄生的红细胞在深层组织微血管中的隔离和两者都导致了一系列 疾病的严重性。这项拟议的研究的目标是了解氧气浓度的波动 在不同组织部位的微环境中，影响P. 恶性疟原虫和诺氏疟原虫。这项研究的发现对我们理解抗疟疾有重要意义。 耐药性，因为一些最重要的抗疟疾药物已被证明通过触发 寄生虫体内ROS的增加，以及对耐药疟原虫的体外研究 不同的氧气浓度表现出不同的结果。虽然众所周知，疟原虫生长得最好 在实验室低氧条件下，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明显慢于13%。 氧气(模拟肺和肝脏中的氧气浓度)与1%的氧气(模拟氧气 在脑和骨髓中的浓度)。共聚焦成像显示13%的人线粒体活性较低 条件。在目标1中，我们将描述这种差异背后的细胞和分子机制(S) 在不同氧气条件下的增殖率，研究不同物种和菌株的这种现象 疟原虫的。我们假设，随着微环境中氧气的增加，细胞内的 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 寄生虫的氧化还原平衡通过调节ROS和P来影响疟原虫的增殖率。 恶性疟原虫的谷胱甘肽抗氧化系统。虽然很多注意力都集中在确定基因突变的特征上 在耐药性的基础上，很少有工作探索宿主环境因素，这些因素也可能在 寄生虫的氧化还原平衡，这可能反过来有助于体内抗疟疾药物的疗效。

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.