Exonuclease-mediated in situ degradation of nascent RNA controls silencing of genes linked to severe malaria

Antigenic variation of the Plasmodium falciparum multicopy var gene family enables parasite evasion of immune destruction by host antibodies 1,2. Expression of a particular var subgroup, termed upsA, is linked to brain blood vessel obstruction and pathogenesis of human cerebral malaria 3-6. The mechanism determining upsA activation remains unknown. Here we show that an entirely new type of gene silencing mechanism involving an exonuclease-mediated degradation of nascent RNA controls silencing of genes linked to severe malaria. We identify a novel chromatin-associated exoribonuclease, termed PfRNase II, that controls silencing of upsA var genes by marking their transcription start site and intron-promoter regions leading to short-lived cryptic RNA. Parasites carrying a deficient PfRNase II gene produce full-length upsA var transcripts and intron-derived antisense long noncoding RNA (lncRNA). The presence of stable upsA var transcripts overcomes monoallelic expression resulting in simultaneous expression of both upsA and upsC type PfEMP1 proteins on the surface of individual infected red blood cells. In addition, we observe an inverse relationship of transcript levels of PfRNase II and upsA-type var genes in parasites from severe malaria patients, implying a critical role of PfRNase II in severe malaria. Our results uncover a previously unknown type of post-transcriptional gene silencing mechanism in malaria parasites with repercussions for other organisms. Additionally, the identification of RNase II as the first parasite protein controlling expression of virulence genes involved in pathogenesis in severe malaria patients may provide new strategies to reduce malaria mortality.