Vacuolar uptake of host components, and a role for cholesterol and sphingomyelin in malarial infection.
Erythrocytes, which are incapable of endocytosis or phagocytosis, can be infected by the malaria parasite Plasmodium falciparum. We find that a transmembrane protein (Duffy), glycosylphosphatidylinositol (GPI)-anchored and cytoplasmic proteins, associated with detergent-resistant membranes (DRMs) that are characteristic of microdomains in host cell membranes, are internalized by vacuolar parasites, while the major integral membrane and cytoskeletal proteins are not. The internalized host proteins and a plasmodial transmembrane resident parasitophorous vacuolar membrane (PVM) protein are detected in DRMs associated with vacuolar parasites. This is the first report of a host transmembrane protein being recruited into an apicomplexan vacuole and of the presence of vacuolar DRMs; it establishes that integral association does not preclude protein internalization into the P.FALCIPARUM: vacuole. Rather, as shown for Duffy, intracellular accumulation occurs at the same rate as that seen for a DRM-associated GPI-anchored protein. Furthermore, novel mechanisms regulated by the DRM lipids, sphingomyelin and cholesterol, mediate (i) the uptake of host DRM proteins and (ii) maintenance of the intracellular vacuole in the non-endocytic red cell, which may have implications for intracellular parasitism and pathogenesis.
Lauer
S
S
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
VanWye
J
J
Harrison
T
T
McManus
H
H
Samuel
B U
BU
Hiller
N L
NL
Mohandas
N
N
Haldar
K
K
D000818:Animals; D000953:Antigens, Protozoan; D015415:Biomarkers; D018957:CD59 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D002784:Cholesterol / Q000172:deficiency / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004705:Endocytosis; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology*; D005372:Filipin / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D007700:Kinetics; D008288:Malaria / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D008563:Membrane Lipids / Q000378:metabolism; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000166:cytology* / Q000502:physiology; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface / Q000378:metabolism; D013109:Sphingomyelins / Q000096:biosynthesis / Q000378:metabolism*; D014617:Vacuoles / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D000953:Antigens, Protozoan; D015415:Biomarkers; D018957:CD59 Antigens; D002352:Carrier Proteins; D003902:Detergents; C066001:Duffy antigen binding protein, Plasmodium; D017261:Glycosylphosphatidylinositols; D008563:Membrane Lipids; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D013109:Sphingomyelins; D005372:Filipin; D002784:Cholesterol