Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

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 undergoART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2 alpha (eIF2 alpha), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2 alpha correlates with high rates of recrudescence following ART, and inhibiting eIF2 alpha dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2 alpha phosphorylation is mediated by the Plasmodium eIF2 alpha 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.