Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance.
Erythrocytes carrying a variant hemoglobin allele (HbS), which causes sickle cell disease and resists infection by the malaria parasite Plasmodium falciparum. The molecular basis of this resistance, which has long been recognized as multifactorial, remains incompletely understood. Here we show that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. During the intraerythrocytic life cycle of P. falciparum, a subset of erythrocyte miRNAs translocate into the parasite. Two miRNAs, miR-451 and let-7i, were highly enriched in HbAS and HbSS erythrocytes, and these miRNAs, along with miR-223, negatively regulated parasite growth. Surprisingly, we found that miR-451 and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading, resulted in translational inhibition. Hence, sickle cell erythrocytes exhibit cell-intrinsic resistance to malaria in part through an atypical miRNA activity, which may represent a unique host defense strategy against complex eukaryotic pathogens.
The Institute for Genome Sciences and Policy, Duke University School of Medicine, Durham, NC 27710, USA.
Gregory
G
LaMonte
Nisha
N
Philip
Joseph
J
Reardon
Joshua R
JR
Lacsina
William
W
Majoros
Lesley
L
Chapman
Courtney D
CD
Thornburg
Marilyn J
MJ
Telen
Uwe
U
Ohler
Christopher V
CV
Nicchitta
Timothy
T
Haystead
Jen-Tsan
JT
Chi
D001692:Biological Transport; D002478:Cells, Cultured; D015536:Down-Regulation; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006451:Hemoglobin, Sickle / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics* / Q000378:metabolism / Q000469:parasitology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D014176:Protein Biosynthesis
D006451:Hemoglobin, Sickle; D035683:MicroRNAs