Malaria Parasites Hijack Immune Host Splicing Machinery Using Decoy RNAs

Malaria, the most serious mosquito-borne parasitic disease, is mainly caused by the lethal parasite Plasmodium falciparum (Pf), which grows within human red blood cells (RBCs). This master of survival is known for utilizing sophisticated defense strategies to alter the host's immune response. Here, we discovered a new Pf virulence mechanism: the parasite delivers three of its own mRNAs, which belong to the ETRAMP family, to human immune system monocytes, where they are rapidly imported into the host cell nucleus. To further determine whether these parasitic transcripts specifically bind to host proteins in the nucleus, we established an RNA antisense purification (RAP) assay. Remarkably, we identified two host nuclear proteins that are strongly bound by Pf mRNAs: ACIN1 (Acinus) and PNN (Pinin). These two proteins play an important role in host mRNA maturation and splicing and are associated with the exon junction complex. The interaction of Pf mRNAs with these nuclear proteins first impedes the translation of target host proteins, initiating a decoy mechanism, and ultimately leads to a shift in the host immune response towards a pro-inflammatory state. This virulence-promoting strategy represents a new layer of survival defense by the deadliest malaria parasite.