The malaria chemical atlas: Revealing the parasite-host functional interactome

Projektinformationen

MalChemAtlas

ID Finanzhilfevereinbarung: 101086598

DOI

10.3030/101086598

EK-Unterschriftsdatum 11 April 2023

Startdatum 1 Oktober 2023

Enddatum 30 September 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 2 000 000,00

EU-Beitrag

€ 2 000 000,00

Koordiniert durch

WEIZMANN INSTITUTE OF SCIENCE
Israel

Periodic Reporting for period 1 - MalChemAtlas (The malaria chemical atlas: Revealing the parasite-host functional interactome)

Berichtszeitraum: 2023-10-01 bis 2026-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Malaria, caused by Plasmodium falciparum (Pf), is the most devastating parasitic disease affecting hundreds of millions of people worldwide. The parasite’s transmission cycle between humans and mosquitoes involves a remarkable series of morphological transformations. While it is clear that, for such a complex journey, the intracellular parasites must develop means to sense their host and coordinate their actions; these modes of communication remain one of the greatest mysteries in malaria biology. In fact, since an individual parasite is enclosed by three membranes inside its human host, the red blood cell (RBC), they were not thought to possess any communication ability. However, we discovered that these parasites, despite the multiple barriers, are able to communicate and exchange episomal genes by releasing extracellular vesicles (EVs), thereby opening the exciting new field of malaria parasite communication. With ERC funding support, our lab aims to take an innovative approach to the underexplored field of malaria parasite communication and sensing pathways. We seek to unravel the complex parasite-host signaling networks by defining the biological roles of parasite-derived vesicles in communication and exploring an additional mode of chemical signalling through secreted small molecules. Our goal is to build a comprehensive view of parasite communication and social behaviour while identifying new therapeutic targets. Using a multidisciplinary approach, integrating biochemistry, biophysics, genetics, chemistry, omics, and molecular biology, we have uncovered new insights into parasite cell-communication biology and continue advancing this emerging field.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

How parasite-derived extracellular vesicles (EVs) enter specific immune cell types within the body remains poorly understood. Using imaging flow cytometry combined with machine learning, we found that parasite EVs employ distinct entry routes depending on the host cell type. In T cells, which are part of the adaptive immune system, EVs primarily interact with and enter through a fusion-like mechanism. In contrast, monocytes, which belong to the innate immune system, internalize these EVs mainly through endocytosis. We further showed that EV uptake is governed by the physical properties of the cell membrane, and that the balance between these two uptake pathways is also affected by the mechanical characteristics of the target cell membrane. Finally, we found that cholesterol levels in the plasma membrane are a key factor guiding the preferred route of EV entry.
Together, these findings reveal how Plasmodium falciparum–derived EVs exploit the distinct membrane features of different host immune cells to ensure targeted delivery. This work provides new mechanistic insights into the sophisticated communication strategies used by the malaria parasite.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We developed a new method to analyze the contents of extracellular vesicles (EVs) released from Plasmodium falciparum–infected red blood cells. Using advanced spectral flow cytometry, we were able to reliably detect these secreted EVs. By labeling both the EV membrane lipids and the DNA cargo inside (without using antibodies), we identified a group of parasite-derived EVs that are rich in DNA. We also measured how many DNA-containing EVs were released during two different parasite blood stages — rings and trophozoites. Our results demonstrate that spectral flow cytometry can be a powerful tool to track changes in the DNA content of EVs produced by pathogens.