Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes.
Plasmodium falciparum infections can cause severe malaria, but not every infected person develops life-threatening complications. In particular, carriers of the structural haemoglobinopathies S and C and infants are protected from severe disease. Protection is associated with impaired parasite-induced host actin reorganization, required for vesicular trafficking of parasite-encoded adhesins, and reduced cytoadherence of parasitized erythrocytes in the microvasculature. Here we show that aberrant host actin remodelling and the ensuing reduced cytoadherence result from a redox imbalance inherent to haemoglobinopathic and fetal erythrocytes. We further show that a transient oxidative insult to wild-type erythrocytes before infection with P. falciparum induces the phenotypic features associated with the protective trait of haemoglobinopathic and fetal erythrocytes. Moreover, pretreatment of mice with the pro-oxidative nutritional supplement menadione mitigate the development of experimental cerebral malaria. Our results identify redox imbalance as a causative principle of protection from severe malaria, which might inspire host-directed intervention strategies.
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Marek
M
Cyrklaff
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Sirikamol
S
Srismith
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Britta
B
Nyboer
Faculty of Physics and Applied Computer Science, AGH-University of Science and Technology in Kraków, Al. Mickiewicza 30, 30-059 Kraków, Poland.
Kvetoslava
K
Burda
Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.|Division of Experimental Radiology, Department of Neuroradiology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Angelika
A
Hoffmann
German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.|Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
Felix
0000-0002-3212-1881
F
Lasitschka
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Sophie
S
Adjalley
Biomolecular Research Center Pietro Annigoni, University of Ouagadougou, 01 BP 364 Ouagadougou, Burkina Faso.
Cyrille
C
Bisseye
Biomolecular Research Center Pietro Annigoni, University of Ouagadougou, 01 BP 364 Ouagadougou, Burkina Faso.
Jacques
J
Simpore
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
Ann-Kristin
AK
Mueller
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Cecilia P
CP
Sanchez
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.
Friedrich
F
Frischknecht
Center of Infectious Diseases, Parasitology, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany.|German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
Michael
0000-0002-0220-6526
M
Lanzer
D000199:Actins / Q000378:metabolism; D000755:Anemia, Sickle Cell / Q000097:blood*; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology* / Q000648:ultrastructure; D005260:Female; D005333:Fetus / Q000473:pathology*; D006454:Hemoglobins / Q000378:metabolism; D016778:Malaria, Falciparum / Q000469:parasitology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D010962:Plasmodium berghei / Q000187:drug effects / Q000502:physiology; D010963:Plasmodium falciparum / Q000378:metabolism / Q000648:ultrastructure; D024483:Vitamin K 3 / Q000494:pharmacology
D000199:Actins; D006454:Hemoglobins; D024483:Vitamin K 3