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Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum

Thomas C. A. Blake, Silvia Haase, View ORCID ProfileJake Baum
doi: https://doi.org/10.1101/2020.06.25.171900
Thomas C. A. Blake
1Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
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Silvia Haase
1Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
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Jake Baum
1Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK
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  • ORCID record for Jake Baum
  • For correspondence: jake.baum@imperial.ac.uk
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Summary

All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the Plasmodium spp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. In Plasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 25, 2020.
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Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum
Thomas C. A. Blake, Silvia Haase, Jake Baum
bioRxiv 2020.06.25.171900; doi: https://doi.org/10.1101/2020.06.25.171900
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Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum
Thomas C. A. Blake, Silvia Haase, Jake Baum
bioRxiv 2020.06.25.171900; doi: https://doi.org/10.1101/2020.06.25.171900

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