Defining the mechanism of coma in cerebral malaria

摘要 疟疾仍然是一个重大的公共卫生挑战，抵制了世界范围的控制努力。一些个人 感染恶性疟原虫的人会发展成脑型疟疾（CM），表现为昏迷 并且与高发病率和死亡率相关。CM昏迷的病因在幸存者中是可逆的， 仍然未知。我们已经确定了高水平的哌可酸（PA）的儿童与CM相比， 轻度疟疾PA已被证明在动物模型中诱导昏迷，我们将测试高PA的假设。 CM中的血液水平导致PA中枢神经系统（CNS）浓度异常升高，从而导致昏迷 在CM中。我们将确定CM与非CM病例相比，PA脑脊液是否升高 脑病我们将确定PA是否在感染伯氏疟原虫ANKA的小鼠脑中富集， 在实验性脑型疟疾模型中，而在感染约氏疟原虫和疟原虫株的小鼠脑中则没有。 chabaudi，它们是小鼠保持清醒的感染模型。我们将研究一个假设， PA通过γ-氨基丁酸（GABA）受体降低意识，这已经被先前的研究所提出。 使用大鼠模型的研究。PA已经被包括我们在内的多个小组证明是由疟原虫产生的， 其在寄生生物学中的作用尚不清楚。我们将确定产生PA的代谢途径，并测试 PA是否保护疟原虫免受氧化应激，类似于在 哺乳动物细胞总的来说，我们的目标是定义PA在昏迷诱导和寄生虫生物学中的作用， 表征人类昏迷的新机制，潜在地鉴定昏迷的CM病因学的生物标志物， 并描述了一个潜在的新的目标，以改善CM的健康结果。

ABSTRACT Malaria remains a significant public health challenge that has resisted worldwide control efforts. Some individuals who become infected with Plasmodium falciparum develop cerebral malaria (CM), which presents as a coma and is associated with high morbidity and mortality. The etiology of CM coma, which is reversible in survivors, remains unknown. We have identified high blood levels of pipecolic acid (PA) in children with CM compared to mild malaria. PA has been shown to induce coma in animal models, and we will test the hypothesis that high blood levels in CM result in abnormally elevated PA central nervous system (CNS) concentrations to result coma in CM. We will determine if PA cerebral spinal fluids are elevated in CM compared with defined non-CM cases of encephalopathy. We will determine if PA is enriched in the brain of mice in infected with P. berghei ANKA in the experimental cerebral malaria model and not in the brains of mice infected with strains P. yoelii and P. chabaudi, which are infection models where mice maintain wakefulness. We will investigate the hypothesis that PA reduces consciousness through γ-aminobutyric acid (GABA) receptors, which has been suggested by prior studies using a rat model. PA has been shown by multiple groups including ours to be produced by Plasmodium, and its role in parasite biology is unknown. We will define the metabolic pathway that produces PA and test whether PA protects the malaria parasite from oxidative stress, similar to its protective role observed in mammalian cells. Overall, our goals are to define the role of PA in coma induction and parasite biology to characterize a novel mechanism of coma in humans, potentially identify a biomarker of CM etiology of coma, and characterize a potential novel target for improving the health outcomes of CM.