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Of membranes and malaria: phospholipid asymmetry in Plasmodium falciparum-infected red blood cells

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Abstract

Malaria is a vector-borne parasitic disease with a vast impact on human history, and according to the World Health Organisation, Plasmodium parasites still infect over 200 million people per year. Plasmodium falciparum, the deadliest parasite species, has a remarkable ability to undermine the host immune system and cause life-threatening disease during blood infection. The parasite’s host cells, red blood cells (RBCs), generally maintain an asymmetric distribution of phospholipids in the two leaflets of the plasma membrane bilayer. Alterations to this asymmetry, particularly the exposure of phosphatidylserine (PS) in the outer leaflet, can be recognised by phagocytes. Because of the importance of innate immune defence numerous studies have investigated PS exposure in RBCs infected with P. falciparum, but have reached different conclusions. Here we review recent advancements in our understanding of the molecular mechanisms which regulate asymmetry in RBCs, and whether infection with the P. falciparum parasite results in changes to PS exposure. On the balance of evidence, it is likely that membrane asymmetry is disrupted in parasitised RBCs, though some methodological issues need addressing. We discuss the potential causes and consequences of altered asymmetry in parasitised RBCs, particularly for in vivo interactions with the immune system, and the role of host-parasite co-evolution. We also examine the potential asymmetric state of parasite membranes and summarise current knowledge on the parasite proteins, which could regulate asymmetry in these membranes. Finally, we highlight unresolved questions at this time and the need for interdisciplinary approaches to uncover the machinery which enables P. falciparum parasites to hide in mature erythrocytes.

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Acknowledgements

The authors would like to thank Andreas Herrmann for insightful discussions. This work was supported by the Alliance Berlin Canberra “Crossing Boundaries: Molecular Interactions in Malaria” which is co-funded by a grant from the Deutsche Forschungsgemeinschaft (DFG) for the International Research Training Group (IRTG) 2290 and the Australian National University. Work in the Maier group is also supported by the Australian Research Council (DP180103212). M.F. is the recipient of an Australian Government Research Training Program Scholarship. The authors declare that they have no conflict of interest.

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  1. Research School of Biology, The Australian National University, Canberra, Australia

    Merryn Fraser & Alexander G. Maier

  2. Department of Molecular Parasitology, Institute of Biology, Humboldt University, Berlin, Germany

    Merryn Fraser & Kai Matuschewski

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18_2021_3799_MOESM1_ESM.docx

Table S1: Published studies which investigated membrane asymmetry in red blood cells infected with P. falciparum (iRBCs) and uninfected RBCs (uRBCs). Only results from RBCs not treated with modifying agent (drug, peptide, heat stress etc.) are shown. Percentages were calculated from tables or graphs using ImageJ where not specified in the text. PS phosphatidylserine; PE phosphatidylethanolamine; PC phosphatidylcholine; SM sphingomyelin; ATP adenosine triphosphate; enriched parasitaemias: increased by isolating iRBCs; effective parasitaemias: differentiated by DNA stain. (DOCX 30 KB)

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Fraser, M., Matuschewski, K. & Maier, A.G. Of membranes and malaria: phospholipid asymmetry in Plasmodium falciparum-infected red blood cells. Cell. Mol. Life Sci. 78, 4545–4561 (2021). https://doi.org/10.1007/s00018-021-03799-6

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