TY - JOUR
T1 - Translocation of sickle cell erythrocyte MicroRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance
AU - Lamonte, Gregory
AU - Philip, Nisha
AU - Reardon, Joseph
AU - Lacsina, Joshua R.
AU - Majoros, William
AU - Chapman, Lesley
AU - Thornburg, Courtney D.
AU - Telen, Marilyn J.
AU - Ohler, Uwe
AU - Nicchitta, Christopher V.
AU - Haystead, Timothy
AU - Chi, Jen Tsan
PY - 2012/8/16
Y1 - 2012/8/16
N2 - 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.
AB - 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.
U2 - 10.1016/j.chom.2012.06.007
DO - 10.1016/j.chom.2012.06.007
M3 - Article
C2 - 22901539
AN - SCOPUS:84865151210
SN - 1931-3128
VL - 12
SP - 187
EP - 199
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -