The role of plasma membrane calcium ATPase 4 (PMCA4) in modulating Plasmodium infection and malaria severity

疟疾是包括印度尼西亚在内的世界许多地区的一个主要公共卫生问题，估计每年造成1.5亿-3亿临床病例，并导致超过43万人死亡(世卫组织报告，2015年)。控制疟疾的战略已显示出一些成功，包括对感染者进行抗疟疾治疗，应用杀虫剂减少蚊子数量，减少人类通过蚊帐与受感染蚊子的接触。然而，寄生虫对现有抗疟疾药物的耐药性迅速传播，阻碍了过去几年在疟疾控制方面的大规模努力。需要开发针对新的生化途径的新的抗疟疾药物，以避免交叉耐药。最近在人类群体中的遗传学研究发现，一种名为PMCA4的钙泵存在于人类红细胞和血管(内皮)细胞中，与抗疟疾感染和脑疟疾的发生密切相关。这些发现意味着PMCA4可被用作抗疟疾治疗和减少脑型疟疾的可能靶点，脑型疟疾是这种疾病最致命的并发症。通过曼彻斯特大学和印度尼西亚艾克曼研究所的科学家合作进行的初步观察表明，使用抑制PMCA4活性的药物治疗可能会减少小鼠模型和细胞培养系统中的疟疾感染。基于这一有希望的初步结果，在这个项目中，我们将进一步研究：1)在小鼠中从基因上抑制PMCA4是否会抑制疟疾寄生虫(疟原虫)的生长并减少实验性脑疟疾的发生2)使用有效和特异的药物抑制PMCA4将抑制小鼠中疟疾寄生虫(疟原虫)的生长并减少实验性脑疟疾的发生3)在印尼人群中PMCA4基因的遗传变异与对疟疾的抵抗力和疾病的严重程度有关。如果我们的假设是正确的，该项目可能为疟疾治疗确定一个新的药理靶点。

Malaria is a major public health problem in many parts of the world including Indonesia, causing an estimated 150-300 million clinical cases and killing more than 430 thousand people annually (WHO Report, 2015). Strategies to control malaria that have demonstrated some success include anti-malaria treatment for infected individuals, application of insecticide to reduce mosquito populations, and reduction of human contact with infected mosquitoes via bednets. However, the rapid spread of parasite resistance to the currently available anti-malarial drugs has hampered large-scale efforts at malaria control within the last few years. Development of new anti-malarial drugs that target novel biochemical pathways is needed to avoid cross resistance.Recent genetic studies in human populations have identified a calcium pump called PMCA4 that is present in human red blood cells and in cells lining the blood vessels (endothelium) to have a very strong association with resistance against malaria infection and the occurrence of brain malaria. These findings imply that PMCA4 can be used as a possible target for anti-malaria treatment and for the reduction of cerebral malaria, the most deadly complication of this disease. Pilot observations conducted through a collaboration between scientists at The University of Manchester and Eijkman Institute Indonesia have demonstrated that treatment with drugs that inhibit PMCA4 activity might reduce malaria infection in a mouse model as well as in a cell culture system. Based on this promising preliminary result, in this project we will further investigate whether: 1) Inhibition of PMCA4 genetically in mice will inhibit the growth of malaria parasite (Plasmodium) and reduce the occurrence of experimental brain malaria 2) Inhibition of PMCA4 using a potent and specific pharmacological inhibitor will inhibit the growth of malaria parasite (Plasmodium) in mice and reduce the occurrence of experimental brain malaria 3) In the Indonesian population genetic variations in the PMCA4 gene are associated with resistance against malaria and severity of the disease.It is expected that this study will provide new information on how malaria infection is regulated at the molecular level. If our hypothesis is correct this project may identify a novel pharmacological target for malaria treatment.