Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells

TY - JOUR

T1 - Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells

AU - Fraser, Merryn

AU - Jing, Weidong

AU - Bröer, Stefan

AU - Kurth, Florian

AU - Sander, Leif-Erik

AU - Matuschewski, Kai

AU - Maier, Alexander G

PY - 2021/2

Y1 - 2021/2

N2 - The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.

AB - The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design.

KW - Calcium/metabolism

KW - Erythrocyte Membrane/metabolism

KW - Erythrocytes/metabolism

KW - Humans

KW - Malaria, Falciparum/metabolism

KW - Monocytes/metabolism

KW - Phagocytosis

KW - Phosphatidylserines/metabolism

KW - Plasmodium falciparum/isolation & purification

U2 - 10.1371/journal.ppat.1009259

DO - 10.1371/journal.ppat.1009259

M3 - SCORING: Journal article

C2 - 33600495

VL - 17

JO - PLOS PATHOG

JF - PLOS PATHOG

SN - 1553-7366

IS - 2

M1 - e1009259

ER -