Center for the Study of Complex Malaria in India

项目3：总结 恶性疟疾是发展中国家死亡和发病的一个主要原因。 脑型疟疾(CM)是其最严重的形式，占疟疾相关死亡的大部分。这个 这种复杂的神经综合征的病理生理学和分子机制仍然很差。 明白了。CM主要影响低传播环境的成人(亚洲)和高传播环境的儿童 变速箱设置(非洲)。两个年龄组的临床表现不同，这表明 病理可能是不同的。两者心肌病病理生理学的严密比较 然而，地理上不同的区域从未被执行过。项目3将使用磁共振 影像(MRI)技术在研究CM发病机制中的首次全面对比分析 在印度劳尔凯拉和布兰太尔的患者之间，MalaŵI。这项研究将利用核磁共振的存在 两个部位的扫描仪，以及镜像临床方案的使用，其中包括视网膜检查， 做了一系列核磁共振扫描，并进行了随访。Raurkela核磁共振扫描仪的较高磁场强度将 也使我们能够评估细胞源性和血管源性水肿在CM合并脑部疾病患者中的各自作用 肿胀。同时，我们将对大脑进行详尽和互补的描述 经眼科和MRI鉴定的不同类型致死性成人CM的病理 考试。我们将使用一种技术，通过采样脑组织来使全面尸检变得不必要。 通过已故病人的眶上板。然后我们将评估血液之间的潜在联系- 成人CM患者的脑屏障受损、视网膜病变和脑肿胀。调查结果将与那些 最近在MalaŵI中类似定义明确的队列中获得，使用相同的技术和读出 参数。最后，我们将研究寄生虫的毒力因子和宿主分子决定因素是如何驱动 来自印度和MARAŵI的患者的CM病理生理学。为此，我们将应用高级机器学习 两个人群的CM疾病病因模型，由临床(神经成像、眼底检查、 凝血因子等)实验室(寄生虫var基因转录分析、血浆生物标记物等) 调查。作为研究寄生虫毒力因素的一部分，我们将测试严重脑损伤的假设 肿胀和视网膜病变与高水平的内皮蛋白C受体(EPCR)结合寄生虫有关 对活化蛋白C(APC)-EPCR保护通路具有很强的阻断活性。其主要结果是 这个项目将更好地了解儿童和儿童的不同致病过程 成人CM，将指导新的辅助疗法的发展。

PROJECT 3: SUMMARY Plasmodium falciparum malaria is a major cause of mortality and morbidity in the developing world and cerebral malaria (CM), its most severe form, accounts for the majority of malaria-associated deaths. The pathophysiology and the molecular mechanisms underlying this complex neurologic syndrome are still poorly understood. CM predominantly affects adults in lower transmission settings (Asia) and children in high- transmission settings (Africa). Clinical presentations differ between the two age groups, suggesting that pathologies may be dissimilar. Rigorous comparisons of the pathophysiology of CM between the two geographically distinct areas have, however, never been performed. Project 3 will use magnetic resonance imaging (MRI) techniques to study CM pathogenesis in the first comprehensive comparative analysis of its kind between patients in Raurkela, India and Blantyre, Malaŵi. The study will leverage the presence of MRI scanners at both sites, as well as the use of mirroring clinical protocols, which include retinal examinations, serial MRI scans, and a follow-up visit. The higher magnetic field strength of the MRI scanner in Raurkela will also allow us to assess the respective roles of cytogenic vs. vasogenic edema in CM patients with cerebral swelling. In parallel, we will carry out an exhaustive and complementary characterization of the cerebral pathologies in different categories of fatal adult CM cases, identified through ophthalmologic and MRI examinations. We will use a technique that renders full autopsies unnecessary by sampling brain tissue through the supraorbital plate of deceased patients. We will then assess the potential links between blood- brain barrier impairment, retinopathies, and brain swelling in adult CM. Findings will be compared with those recently obtained in a similarly well-defined cohort in Malaŵi, using identical techniques and read-out parameters. Lastly, we will investigate how parasite virulence factors and host molecular determinants drive CM pathophysiology in patients from India and Malaŵi. For this, we will apply advanced machine-learning models of CM disease causation in both populations, informed by clinical (neuroimaging, fundus examination, coagulation factors, etc.) and laboratory (parasite var gene transcript analysis, plasma biomarkers, etc.) investigations. As part of investigating parasite virulence factors, we will test the hypothesis that severe brain swelling and retinopathies are linked to high levels of endothelium protein C receptor (EPCR)-binding parasites with strong blockade activity for activated protein C (APC)-EPCR protective pathways. The primary outcome of this project will be a better understanding of the different pathogenetic processes involved in pediatric and adult CM, which will guide the development of new adjunct therapies.