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，每年造成约1.5亿至3亿临床病例，造成43万人死亡（世卫组织报告，2015年）。已取得一定成功的疟疾控制战略包括：对受感染个体进行抗疟疾治疗，使用杀虫剂减少蚊子数量，以及通过蚊帐减少人类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蔓延，在过去几年中阻碍了疟疾控制的大规模努力。为了避免交叉耐药，需要开发针对新的生化途径的新型抗疟疾药物。最近在人群中进行的遗传研究发现，一种名为PMCA4的钙泵存在于人类红细胞和血管内壁细胞（内皮）中，与抵抗疟疾感染和发生脑疟疾有很强的关联。这些发现意味着PMCA4可以作为抗疟疾治疗和减少脑疟疾（这种疾病最致命的并发症）的可能靶点。通过曼彻斯特大学和印度尼西亚Eijkman研究所的科学家之间的合作进行的初步观察表明，用抑制PMCA4活性的药物治疗可能减少小鼠模型以及细胞培养系统中的疟疾感染。基于这个有希望的初步结果，在本项目中，我们将进一步研究是否：1)在小鼠体内基因抑制PMCA4可抑制疟原虫（疟原虫）的生长，减少实验性脑疟疾的发生2)利用强效特异性药物抑制剂抑制PMCA4可抑制小鼠体内疟原虫（疟原虫）的生长，减少实验性脑疟疾的发生3)在印度尼西亚人群中PMCA4基因的遗传变异与疟疾耐药性和疾病严重程度相关。预计该研究将为疟疾感染如何在分子水平上调控提供新的信息。如果我们的假设是正确的，这个项目可能会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.