Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Abstract

Summary Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection.

The endoplasmic reticulum chaperone PfGRP170 is essential for asexual development and is linked to stress response in malaria parasites

“…However, several ER localised stress response pathways present in other eukaryotes are absent in P. falciparum, and few molecular players in the parasite ER stress response pathway are known. The Plasmodium genome does not encode many of the UPR orthologues, but a single ER stress pathway (PK4 signalling) has been previously described and was shown to be activated following artemisinin treatment (Zhang et al, 2012;Zhang et al, 2017). This finding highlights a potential critical role for PfGRP170 in vivo, as high febrile episodes are one of the main symptoms of clinical malaria and are considered a defence mechanism against parasites.…”

“…Moreover, we demonstrate here that PfGRP170 interacts with the Plasmodium homologue of BiP (PF3D7_0917900) suggesting a conserved HSP70 ER chaperone complex. Finally, we show that conditional inhibition of PfGRP170 leads to the activation of the only known ER stress response pathway in Plasmodium, the PK4 pathway (Zhang et al, 2012;Zhang et al, 2017).…”

“…The only identified ER stress response pathway in Plasmodium is the PERK/PK4 pathway (Zhang et al, 2012;Zhang et al, 2017). When the ER is stressed, PK4 oligomerises and becomes active, phosphorylating the cytoplasmic translation initiation factor EIF2-α to halt translation and flux through the ER (Zhang et al, 2012;Zhang et al, 2017). Under normal conditions, PK4 exists as a transmembrane monomeric protein in the ER.…”

“…Plasmodium lack much of the ER machinery used to activate stress response pathways (Chaubey, Grover, & Tatu, 2014;Harbut et al, 2012;Zhang et al, 2012). The only identified ER stress response pathway in Plasmodium is the PERK/PK4 pathway (Zhang et al, 2012;Zhang et al, 2017). Signalling through this pathway has been shown to occur in the parasite following artemisinin treatment (Zhang et al, 2017).…”

“…The only identified ER stress response pathway in Plasmodium is the PERK/PK4 pathway (Zhang et al, 2012;Zhang et al, 2017). Signalling through this pathway has been shown to occur in the parasite following artemisinin treatment (Zhang et al, 2017). Under normal conditions, PK4 exists as a transmembrane monomeric protein in the ER.…”