HEИндивидуална стипендия2023–2025

MAL-ZOO · The malaria zoo: dissecting cerebral malaria in three in vitro primate blood-brain barrier models

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-04-01 → 2025-03-31
Финансиране от ЕС: 180 097 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите на церебралната малария се изучават чрез лабораторни модели на кръвно-мозъчната бариера, създадени от човешки стволови клетки. Разбирането на процесите, при които паразитите увреждат мозъчните съдове, е важно за откриването на нови стратегии за намаляване на високата смъртност.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

The malaria zoo: dissecting cerebral malaria in three in vitro primate blood-brain barrier models

Malaria is a parasitic disease that continues to affect hundreds of millions of people every year, causing over 600,000 deaths, mostly among children in sub-Saharan Afrihttps://ec.europa.eu/research/participants/grants-app/reporting/VAADIN/themes/sygma/icons/ico6-save.pngca. Although the numbers of infections and deaths has strongly decreased in recent decades, progress in further reducing malaria has stalled. Therefore, advances in our understanding of how the disease develops is essential to finding new strategies to reduce the high mortality. The most severe complication, and the major cause of deaths, particularly in children, is cerebral malaria (CM), with a mortality rate of 15 – 25%. During CM, parasites accumulate in the brain’s blood vessels, where they can damage the blood-brain barrier. This can lead to brain swelling, coma and death. However, the exact mechanism is not entirely understood. Interestingly, CM can occur in certain macaque species, but not in zoonotic malaria (spreading from macaques to humans). This suggests that host-specific factors define the outcome of the disease. A big limitation in studying human CM, is that animal models do not reflect the extent of parasite accumulation and brain swelling seen in patients. In contrast, studies on human patients is limited to non-invasive and post-mortem inspections. To overcome these barriers, tissue engineering is undergoing enormous advances by creating complex tissue models from human cells grown in culture. These in vitro models can replicate key physiological processes, including those involved in CM. A powerful tool for building such models is the use of induced pluripotent stem cells (iPSC). iPSCs can differentiate into all cell types, including those forming our blood vessels. Freshly differentiated cells can self-organize into tissue-like structures and often mimic the behavior of real human tissue. iPSCs can also be derived from specific donors, and therefore allow host-specific disease modelling, using cells of humans or animals like macaques. This project uses iPSCs to study CM by addressing the following objectives: 1. Develop an iPSC-method to generate human brain blood vessel models for in vitro studies of CM. 2. Reproduce key features of CM in the model, such as parasite accumulation and vessel damage, to better understand how infection leads to brain pathology. 3. Adapt the methods to macaque iPSCs to explore species-specific differences during infection. This will help identify mechanisms that either contribute to or protect against CM.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Plasmodium falciparum cerebral malaria (CM) is the most severe complication during malaria infections. CM is associated with patient coma and blood-brain barrier (BBB) disruption resulting in brain swelling and patient death. In the zoonotic malaria parasite P. knowlesi, CM is described in rhesus macaques but occurs neither in human infections nor in the natural long-tail macaque reservoir. Infected red blood cell cytoadhesion to endothelial cells and the release of parasite toxins have been described as pathogenic mechanisms of falciparum CM. Both factors are present in P. knowlesi in all three primate hosts, albeit at different levels and result in different clinical outcomes. Therefore, I hypothesize that the pathogenic mechanisms of CM in primates are host and parasite-specific. As in vivo studies are limited to post mortem samples, I aim to develop in MAL-ZOO novel microvascular 3D in vitro models of the human, rhesus macaque and long tail macaque BBB. I will adapt existing differentiation protocols for human induced pluripotent stem cells (iPSC) to generate macaque endothelial cells, astrocytes and pericytes, that will be introduced in a 3D microvascular model. Taking advantage of the microfluidic properties of the devices, I will characterize the dynamics of P. knowlesi cytoadhesion to the endothelium of the three hosts. Afterwards, I will measure the BBB pathogenicity of these two parasites by confocal microscopy, functional permeability assays and RNAseq transcriptional analysis and correlate it to the parasite cytoadhesion levels. The cross-species comparison will be used to highlight species-specific virulence factors during P. falciparum and P. knowlesi infections. This will improve our understanding of the mechanisms leading to P. falciparum CM in humans and the pathogenic potential of zoonotic P. knowlesi malaria.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания