Center for the Study of Complex Malaria in India

项目3：概要 恶性疟原虫疟疾是发展中国家死亡和发病的主要原因， 脑型疟疾（CM）是其最严重的形式，占疟疾相关死亡的大多数。的 这种复杂的神经系统综合征的病理生理学和分子机制仍然很差， 明白CM主要影响低传播环境中的成年人（亚洲）和高传播环境中的儿童。 传输设置（非洲）。两个年龄组的临床表现不同，表明， 病理可能不同。两者之间CM病理生理学的严格比较 然而，地理上不同的区域从未被执行过。Project 3将使用磁共振技术 影像学（MRI）技术研究CM发病机制的第一个全面的比较分析其种类 在印度的劳凯拉和马拉加的布兰太尔的病人之间。该研究将利用MRI的存在 在两个站点使用扫描仪，以及使用镜像临床协议，其中包括视网膜检查， 连续核磁共振扫描和随访劳凯拉的MRI扫描仪的磁场强度更高， 还使我们能够评估脑血管病患者中细胞源性水肿与血管源性水肿各自的作用。 肿胀.与此同时，我们将对大脑进行详尽和补充的表征， 通过眼科和MRI确定的不同类别致死性成人CM病例的病理学 考试我们将使用一种技术，通过取样脑组织， 穿过死者的眶上板我们会评估血液和- 脑屏障损伤、视网膜病变和脑肿胀。调查结果将与那些 最近在马拉加的一个类似的明确定义的队列中获得，使用相同的技术和读出 参数最后，我们将研究寄生虫毒力因子和宿主分子决定簇如何驱动 印度和马拉维患者的CM病理生理学。为此，我们将应用先进的机器学习 两个群体中CM疾病病因的模型，通过临床（神经成像，眼底检查， 凝血因子等）和实验室（寄生虫var基因转录分析，血浆生物标志物等） 调查事务所作为研究寄生虫毒力因子的一部分，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保护途径具有强阻断活性。的主要结局 该项目将更好地了解儿科和儿科疾病的不同发病过程， 成人CM，这将指导新的辅助治疗的发展。

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.