Long Noncoding RNAs Maintain Antigenic Variation in the Malaria Parasite

Control of DNA expression by long noncoding RNAs has been found to underlie antigenic variation, the mechanism by which the malaria parasite Plasmodium falciparum maintains its virulence and evades human immune attack.

Long noncoding RNAs (long ncRNAs, lncRNA) are non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes lncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. While lncRNAs are known to be involved in numerous biological roles including imprinting, epigenetic gene regulation, cell cycle and apoptosis, and metastasis and prognosis in solid tumors, their function in parasitic diseases has not been clarified.

Plasmodium falciparum expresses its primary virulence determinants in a mutually exclusive manner and evades human immune attack through switches in expression between different variants of a large gene family named var. Investigators at the Hebrew University of Jerusalem (Israel) sought an explanation as to how P. falciparum was able to express only one var gene at a time while the rest of the family was maintained silenced.

They reported in the February 17, 2015, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that antisense lncRNAs initiating from var introns were associated with the single active var gene at the time in the cell cycle when the single var upstream promoter was active. These antisense transcripts were incorporated into chromatin, and expression of these antisense lncRNAs triggered activation of a silent var gene in a sequence- and dose-dependent manner. On the other hand, interference with these lncRNAs using complement peptide nucleic acid molecules downregulated the active var gene, erased the epigenetic memory, and induced expression switching.

Senior author Dr. Ron Dzikowski, professor of microbiology and molecular genetics at the Hebrew University of Jerusalem, said, “We believe this breakthrough has exposed the tip of the iceberg in understanding how the deadliest malaria parasite regulates the selective expression of its genes, enabling it to evade the immune system. Understanding the mechanisms by which the parasite evades immunity takes us closer to finding ways to either block this ability, or force the parasite to expose its entire antigenic repertoire and thus allow the human immune system to overcome the disease. Such findings can help pave the way for development of new therapies and vaccines for malaria.”

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Hebrew University of Jerusalem