Investigating the role of decay-accelerating factor during red blood cell invasion by Plasmodium falciparum

Abstract

Plasmodium falciparum, responsible for the most severe form of malaria, causes over half a
million deaths annually. Disease symptoms arise during the blood-stage, when parasites invade
red blood cells (RBCs). Whilst several host–parasite interactions have been described there is
little understanding of how host factors facilitate invasion. CD55 was recently proposed as an
essential host receptor, yet its role remains unknown and conflicting reports question its
importance.
This thesis investigates the contribution of CD55 to invasion using two extremely rare natural
CD55-null RBC variants, the Inab phenotype and paroxysmal nocturnal haemoglobinuria
(PNH). Both exhibited a reduced susceptibility to invasion demonstrating the importance of
CD55. However, discrepancies in efficiency highlighted the limitations of these CD55-null
models. Importantly, analysis of the natural mosaic of CD55+ and CD55- RBCs in PNH,
revealed for the first time that parasites preferentially invade CD55+ cells. Artificially mixed
populations confirmed that CD55+ invasion is enhanced by the presence of CD55- cells,
uncovering a selective advantage linked to CD55 expression.
To provide a more tractable system, CD55 knockout reticulocytes were generated from CD34⁺
haematopoietic stem cells and a new co-culture system was developed to promote reticulocyte
maturation. Invasion assays described a subtle, but reproducible contribution of CD55 to
invasion, independent of reticulocyte maturation. Rescue of the KO with CD55 fused to
transmembrane domains fully rescued invasion and revealed that the GPI anchor of CD55 is
not required. Further investigations suggested that CD55 does not act as a direct parasite
receptor, but instead modulates invasion indirectly, with evidence of co-dependency on
basigin. Preliminary TurboID-based biotinylation experiments were also explored to identify
additional surface interactions.
Together, this work clarifies the role of CD55 in P. falciparum invasion as not an essential
receptor, but a positive modulator that enhances parasite selectivity for target cells. By
integrating natural variants, engineered models, and a novel maturation system, this thesis has
helped resolve long-standing questions around the role of CD55 in invasion.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ash M Toye (Supervisor) & Tim J Satchwell (Supervisor)