Plasmodium falciparumGCN5 plays a key role in regulating artemisinin resistance–related stress responses

Abstract

Plasmodium falciparumcauses the most severe malaria and is exposed to various environmental and physiological stresses in the human host. Given that GCN5 plays a critical role in regulating stress responses in model organisms, we aimed to elucidate PfGCN5's function in stress responses inP. falciparum. With TetR-DOZI conditional knockdown (KD) system, we successfully down-regulate PfGCN5 and found that KD parasites became more sensitive to heat shock, low glucose starvation, and dihydroartemisinin (DHA), the active metabolite of all artemisinin (ART) compounds. Transcriptomic analysis via RNA-seq identified 300-400 genes involved in PfGCN5-dependent, general, and stress-specific responses with high levels of overlaps among three stress conditions. Notably, using ring-stage survival assay (RSA), we found that KD or inhibition of PfGCN5 could sensitize the ART-resistant parasites to the DHA treatment. All these indicate that PfGCN5 is pivotal in regulating general and stress-specific responses in malaria parasites, implicating PfGCN5 as a potential target for malaria intervention.