Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells
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Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells. / Fraser, Merryn; Jing, Weidong; Bröer, Stefan; Kurth, Florian; Sander, Leif-Erik; Matuschewski, Kai; Maier, Alexander G.
In: PLOS PATHOG, Vol. 17, No. 2, e1009259, 02.2021.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -