2. Academic Validation
  3. Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria

Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria

  • Cell Host Microbe. 2025 Apr 9;33(4):529-544.e9. doi: 10.1016/j.chom.2025.03.008.
Camila Marques-da-Silva 1,  Clyde Schmidt-Silva 1,  Carson Bowers 2,  Nana Appiah Essel Charles-Chess 1,  Cristina Samuel 2,  Justine C Shiau 3,  Eui-Soon Park 4,  Zhongyu Yuan 5,  Bae-Hoon Kim 4,  Dennis E Kyle 6,  John T Harty 7,  John D MacMicking 4,  Samarchith P Kurup 8
Affiliations

Affiliations

  • 1 Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.
  • 2 Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.
  • 3 Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA.
  • 4 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 5 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 6 Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA.
  • 7 Department of Pathology, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA.
  • 8 Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA. Electronic address: samar@uga.edu.
PMID: 40168996 DOI: 10.1016/j.chom.2025.03.008
Abstract

Plasmodium parasites undergo development and replication within hepatocytes before infecting erythrocytes and initiating clinical malaria. Although type I interferons (IFNs) are known to 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-mediated disruption of the PV activates the Caspase-1 inflammasome, inducing Pyroptosis to remove infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium, with their pharmacologic or genetic inhibition leading to profound malarial susceptibility in vivo. In addition to identifying IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, our study also extends the understanding of how non-immune cells are integral to protective immunity against malaria.

Keywords

LAP; LC3; Plasmodium; cell-autonomous; cell-intrinsic; guanylate-binding protein; innate; liver; lysosome; malaria; reactive oxygen species.

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