MiRNAs and Malaria Resistance

Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance

• Erythrocyte miRNAs are translocated into P falciparum in a sequence-specific manner
• Sickle cell erythrocyte enriched miR-451 and let-7i inhibit parasite growth
• Erythrocyte miRNAs form chimeric transcripts with the 5′ end of parasite mRNAs
• RNA fusion inhibits target parasite mRNA translation

Researchers at Duke University Medical Center may finally have discovered why people with sickle cell disease get milder cases of malaria than individuals who have normal red blood cells.

The paper shows that the dysregulated microRNA (miRNA) composition, of either heterozygous HbAS or homozygous HbSS erythrocytes, contributes to resistance against P. falciparum. ”

“One of the most interesting findings in our study is that the human microRNA found in sickle red cells directly participate in the gene regulation of malaria parasites,” said Dr. Jen-Tsan Chi, M.D., Ph.D., senior author and associate professor in the Duke Institute for Genome Sciences and Policy and Department of Molecular Genetics and Microbiology. “These microRNAs enriched in the sickle red cells reduce the parasite’s ability to propagate, so that certain people stay more protected.”

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. The group found that miR-451 and let-7i integrated into essential parasite messenger RNAs and, via impaired ribosomal loading, resulted in translational inhibition. “If you block the miRNAs, the parasite grows two or three times as well,” Chi said.

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.

Sources:

Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance
Gregory LaMonte, Nisha Philip, Joseph Reardon, Joshua R. Lacsina, William Majoros, Lesley Chapman, Courtney D. Thornburg, Marilyn J. Telen, Uwe Ohler, Christopher V. Nicchitta, Timothy Haystead, Jen-Tsan Chi
Cell Host & Microbe – 16 August 2012 (Vol. 12, Issue 2, pp. 187-199)
http://www.cell.com/cell-host-microbe/abstract/S1931-3128%2812%2900234-X

Duke University Medical Center