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1.5亿至3亿临床病例，并导致超过43万人死亡（WHO报告，2015年）。控制疟疾的战略已经取得了一些成功，包括对受感染者进行抗疟疾治疗，使用杀虫剂减少蚊子数量，以及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抗药性迅速蔓延，在过去几年中阻碍了大规模的疟疾控制工作。为了避免交叉耐药性，需要开发针对新的生化途径的新型抗疟疾药物。最近的人类遗传学研究发现，人体红细胞和血管内皮细胞中存在一种名为PMCA 4的钙泵，这种钙泵与抗疟疾感染和脑疟疾的发生有很强的关联。这些发现意味着PMCA 4可以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。曼彻斯特大学和印度尼西亚Eijkman研究所的科学家合作进行的试点观察表明，使用抑制PMCA 4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。基于这一令人鼓舞的初步结果，在本项目中，我们将进一步研究：1）在小鼠中遗传地抑制PMCA 4将抑制疟原虫的生长（疟原虫）和减少实验性脑疟疾的发生2）使用有效和特异的药理学抑制剂抑制PMCA 4将抑制疟原虫的生长（疟原虫）在小鼠和减少实验性脑疟疾的发生3）在印度尼西亚人群中，PMCA 4基因的遗传变异与疟疾的抵抗力和疾病的严重程度有关。是在分子水平上被调节的。如果我们的假设是正确的，这个项目可能会确定一个新的疟疾治疗的药理学靶点。

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.