A biotin derivative blocks parasite induced novel permeation pathways in Plasmodium falciparum-infected erythrocytes.
The malaria parasite Plasmodium falciparum infects human erythrocytes, and it induces an increased rate of uptake into the infected cell of a range of solutes, including essential nutrients required for parasite development. Several models have been proposed for the mechanism(s) underlying parasite-induced solute uptake, each differing with respect to the site of entry into infected cells. We show that a biotin derivative that is excluded from non-infected erythrocytes gains access to infected erythrocytes via a pathway that is inhibited by compounds shown previously to block the pathways responsible for the increased uptake of solutes. The derivative was found to bind erythrocyte cytoskeletal proteins and to hemoglobin, providing evidence that the novel pathways are in the erythrocyte membrane and allow direct access of solutes to the erythrocyte cytosol. The derivative inhibited its own uptake and blocked the parasite-induced transport of other solutes. In whole-cell patch-clamp analyses, biotinylation of infected erythrocytes caused significant decrease in a parasite-induced outward rectifying conductance. In vitro, biotinylation of trophozoite-stage parasitized erythrocytes delayed parasite development. Treatment of infected cells in the final developmental stage abrogated the parasite's ability to complete development. The data are consistent with the novel pathways playing an important role in parasite growth.
Baumeister
Stefan
S
FB Biology, Philipps-University Marburg, Marburg 35032, Germany.
Endermann
Tobias
T
Charpian
Stefan
S
Nyalwidhe
Julius
J
Duranton
Christophe
C
Huber
Stephan
S
Kirk
Kiaran
K
Lang
Florian
F
Lingelbach
Klaus
K
D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004910:Erythrocyte Membrane / Q000469:parasitology / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology / Q000502:physiology; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D018408:Patch-Clamp Techniques; D010963:Plasmodium falciparum / Q000254:growth & development / Q000472:pathogenicity; D013388:Succinimides / Q000378:metabolism / Q000494:pharmacology*
D013388:Succinimides; C061443:sulfosuccinimidyl 6-(biotinamido)hexanoate; D001710:Biotin