title: Hemoglobin S and C affect protein export in Plasmodium falciparum-infected erythrocytes.
abstract: Malaria is a potentially deadly disease. However, not every infected person develops severe symptoms. Some people are protected by naturally occurring mechanisms that frequently involve inheritable modifications in their hemoglobin. The best studied protective hemoglobins are the sickle cell hemoglobin (HbS) and hemoglobin C (HbC) which both result from a single amino acid substitution in β-globin: glutamic acid at position 6 is replaced by valine or lysine, respectively. How these hemoglobinopathies protect from severe malaria is only partly understood. Models currently proposed in the literature include reduced disease-mediating cytoadherence of parasitized hemoglobinopathic erythrocytes, impaired intraerythrocytic development of the parasite, dampened inflammatory responses, or a combination thereof. Using a conditional protein export system and tightly synchronized Plasmodium falciparum cultures, we now show that export of parasite-encoded proteins across the parasitophorous vacuolar membrane is delayed, slower, and reduced in amount in hemoglobinopathic erythrocytes as compared to parasitized wild type red blood cells. Impaired protein export affects proteins targeted to the host cell cytoplasm, Maurer's clefts, and the host cell plasma membrane. Impaired protein export into the host cell compartment provides a mechanistic explanation for the reduced cytoadherence phenotype associated with parasitized hemoglobinopathic erythrocytes.
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kilian
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Sirikamol
authors.initials: S
authors.lastname: Srismith
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dittmer
authors.affiliation: Biomolecular Research Center Pietro Annigoni, University of Ouagadougou, 01 BP 364 Ouagadougou, Burkina Faso.
authors.forename: Djeneba
authors.initials: D
authors.lastname: Ouermi
authors.affiliation: Biomolecular Research Center Pietro Annigoni, University of Ouagadougou, 01 BP 364 Ouagadougou, Burkina Faso.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Bisseye
authors.affiliation: Biomolecular Research Center Pietro Annigoni, University of Ouagadougou, 01 BP 364 Ouagadougou, Burkina Faso.
authors.forename: Jacques
authors.initials: J
authors.lastname: Simpore
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Cyrklaff
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
authors.forename: Cecilia P
authors.initials: CP
authors.lastname: Sanchez
authors.affiliation: Center of Infectious Diseases, Parasitology, Heidelberg University, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany michael_lanzer@med.uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
keywords: Hemoglobinopathy; Malaria; P. falciparum; Protein export