Investigating the role of oxygen on Plasmodium multiplication rate

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 被寄生的红细胞在深部组织微血管中的隔离， 疾病严重程度。这项研究的目的是了解氧气浓度的波动 在微环境中，它在体内不同的组织部位，影响P的增殖率。 恶性疟原虫和诺氏疟原虫。这项研究的结果对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物已被证明是通过触发 增加活性氧（ROS）的寄生虫，并在体外研究的抗药性疟原虫下， 不同的氧浓度显示出不同的结果。虽然众所周知疟原虫生长得最好 在低氧条件下的实验室中，人们对这种寄生虫在高氧条件下的生物学知之甚少。 氧气条件。我们初步的体外实验数据表明恶性疟原虫的复制速度明显减慢， 氧气（模拟肺和肝脏中的氧气浓度）与1%氧气（模拟氧气 在脑和骨髓中的浓度）。共聚焦成像显示，13%的人的线粒体活性较低， 条件在目标1中，我们将描述变异性背后的细胞和分子机制 在不同氧条件下的增殖率，研究这一现象在不同的物种和菌株 疟原虫。我们假设，随着微环境中氧气的增加，细胞内 随后ROS和细胞损伤，导致增殖率下降。在目标2中，我们将直接测试 疟原虫的氧化还原平衡通过操纵ROS和P影响疟原虫的增殖率。 恶性疟原虫的谷胱甘肽抗氧化系统。虽然人们把注意力集中在基因突变的特征上， 潜在的耐药性，很少有工作探讨宿主环境因素，也可能发挥作用， 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。

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.