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.
