Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria 2178

Abstract Description Plasmodium parasites develop and replicate within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) can hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1 disruption of the PV activates caspase-1 inflammasome, inducing pyroptosis to remove the infected host cells. Remarkably, human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium; their pharmacologic or genetic inhibition led to profound malarial susceptibility, and are essential in vivo. In addition to identifying the IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, this study extends our understanding of how non-immune cells are integral to protective immunity against malaria. Funding Sources NIH/NIAID HHMI Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)