Elimination of intra-hepatocytic malaria parasites is driven by non-canonical autophagy but not nitric oxide production.

Elimination of the malaria parasite intra-hepatocytic liver stages (LS) by innate and adaptive immune cells requires interferon gamma (IFN-γ). The current view in the field posits that IFN-γ-mediated elimination of LS is executed by the induction of intra-hepatocytic nitric oxide (NO). Here, we refute this view and instead show that IFN-γ-driven induction of non-canonical autophagy via gamma-aminobutyric acid receptor-associated proteins (GABARAPs) has a critical functional role in IFN-γ-mediated elimination of LS. Furthermore, mediators of lysosomal maturation and fusion also have important functions in this process. Recruitment of GABARAPs to the LS parasitophorous vacuole (PV) compartment likely promotes the fusion of the PV membrane with lysosomes, thereby leading to elimination of intra-hepatocytic parasites. In contrast, LC3 has an infection-supportive function by protecting LS from GABARAP-mediated elimination. We also found an important role of the reactive oxygen species (ROS)-inducing protein NOX2, indicating a two-pronged host response drives LS elimination.