Malaria parasites release vesicle subpopulations with signatures of different destinations

Paula Abou Karam; Irit Goldian-Rosenheck; Tamar Ziv; Hila Ben Ami; Ido Azuri; Anna Rivkin; Edo Kiper; Ron Rotkopf; Sidney R Cohen; Ana Claudia Torrecilhas; Ori Avinoam; Alicia Rojas; Mattia Morandi; Neta Regev-Rudzki

doi:10.15252/embr.202254755

Malaria parasites release vesicle subpopulations with signatures of different destinations

Paula Abou Karam, Irit Goldian-Rosenheck, Tamar Ziv, Hila Ben Ami, Ido Azuri, Anna Rivkin, Edo Kiper, Ron Rotkopf, Sidney R Cohen, Ana Claudia Torrecilhas, Ori Avinoam, Alicia Rojas, Mattia Morandi^*, Neta Regev-Rudzki^*

^*Corresponding author for this work

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Abstract

Malaria is the most serious mosquito-borne parasitic disease, caused mainly by the intracellular parasite Plasmodium falciparum. The parasite invades human red blood cells and releases extracellular vesicles (EVs) to alter its host responses. It becomes clear that EVs are generally composed of sub-populations. Seeking to identify EV subpopulations, we subject malaria-derived EVs to size-separation analysis, using asymmetric flow field-flow fractionation. Multi-technique analysis reveals surprising characteristics: we identify two distinct EV subpopulations differing in size and protein content. Small EVs are enriched in complement-system proteins and large EVs in proteasome subunits. We then measure the membrane fusion abilities of each subpopulation with three types of host cellular membranes: plasma, late and early endosome. Remarkably, small EVs fuse to early endosome liposomes at significantly greater levels than large EVs. Atomic force microscope imaging combined with machine-learning methods further emphasizes the difference in biophysical properties between the two subpopulations. These results shed light on the sophisticated mechanism by which malaria parasites utilize EV subpopulations as a communication tool to target different cellular destinations or host systems.

Original language	English
Article number	e54755
Number of pages	18
Journal	EMBO Reports
Volume	23
Issue number	7
DOIs	https://doi.org/10.15252/embr.202254755
Publication status	Published - 1 Jun 2022

Funding

We thank the Malaria Research Reference Reagent Resource Center (MR4) for their generous supply of parasite strains. We thank Yael Fridmann Sirkis and the protein analysis unit for their assistance with the AF4 system. We thank Smoler Proteomics center at the Technion—Israel Institute of Technology for their work on EV proteomic analysis. The research of NR‐R is supported by the Benoziyo Endowment Fund for the Advancement of Science, the Jeanne and Joseph Nissim Foundation for Life Sciences Research and the Samuel M. Soref and Helene K. Soref Foundation. NR‐R is the incumbent of the Enid Barden and Aaron J. Jade President's Development Chair for New Scientists in Memory of Cantor John Y. Jade. NRR is grateful for the support from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 757743), the Minerva Program support (grant number 714142), the Weizmann—Sao Paulo Research Foundation (FAPESP) Brazil; supported by a research grant from the Instituto Serrapilheira and the Israel Science Foundation (ISF) (Grant Application no. 570/21). This research was supported by the Israel Science Foundation (ISF) (grant No. 1637/20), within the Israel Precision Medicine Partnership (IPMP) program to O.A. and N.R‐R. O.A. is an incumbent on the Miriam Berman Presidential Development Chair.

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nr_EmboReport_Malariaparasitesrelease_PV_2022Final published version, 2.54 MBLicence: CC BY-NC-ND

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Abou Karam, P., Goldian-Rosenheck, I., Ziv, T., Ben Ami, H., Azuri, I., Rivkin, A., Kiper, E., Rotkopf, R., Cohen, S. R., Torrecilhas, A. C., Avinoam, O., Rojas, A., Morandi, M., & Regev-Rudzki, N. (2022). Malaria parasites release vesicle subpopulations with signatures of different destinations. EMBO Reports, 23(7), Article e54755. https://doi.org/10.15252/embr.202254755

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abstract = "Malaria is the most serious mosquito-borne parasitic disease, caused mainly by the intracellular parasite Plasmodium falciparum. The parasite invades human red blood cells and releases extracellular vesicles (EVs) to alter its host responses. It becomes clear that EVs are generally composed of sub-populations. Seeking to identify EV subpopulations, we subject malaria-derived EVs to size-separation analysis, using asymmetric flow field-flow fractionation. Multi-technique analysis reveals surprising characteristics: we identify two distinct EV subpopulations differing in size and protein content. Small EVs are enriched in complement-system proteins and large EVs in proteasome subunits. We then measure the membrane fusion abilities of each subpopulation with three types of host cellular membranes: plasma, late and early endosome. Remarkably, small EVs fuse to early endosome liposomes at significantly greater levels than large EVs. Atomic force microscope imaging combined with machine-learning methods further emphasizes the difference in biophysical properties between the two subpopulations. These results shed light on the sophisticated mechanism by which malaria parasites utilize EV subpopulations as a communication tool to target different cellular destinations or host systems.",

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AU - Rotkopf, Ron

AU - Cohen, Sidney R

AU - Torrecilhas, Ana Claudia

AU - Avinoam, Ori

AU - Rojas, Alicia

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AB - Malaria is the most serious mosquito-borne parasitic disease, caused mainly by the intracellular parasite Plasmodium falciparum. The parasite invades human red blood cells and releases extracellular vesicles (EVs) to alter its host responses. It becomes clear that EVs are generally composed of sub-populations. Seeking to identify EV subpopulations, we subject malaria-derived EVs to size-separation analysis, using asymmetric flow field-flow fractionation. Multi-technique analysis reveals surprising characteristics: we identify two distinct EV subpopulations differing in size and protein content. Small EVs are enriched in complement-system proteins and large EVs in proteasome subunits. We then measure the membrane fusion abilities of each subpopulation with three types of host cellular membranes: plasma, late and early endosome. Remarkably, small EVs fuse to early endosome liposomes at significantly greater levels than large EVs. Atomic force microscope imaging combined with machine-learning methods further emphasizes the difference in biophysical properties between the two subpopulations. These results shed light on the sophisticated mechanism by which malaria parasites utilize EV subpopulations as a communication tool to target different cellular destinations or host systems.

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Malaria parasites release vesicle subpopulations with signatures of different destinations

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