Journal article
Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria
Cell host & microbe, Vol.33(4), pp.529-544.e9
04/09/2025
DOI: 10.1016/j.chom.2025.03.008
PMID: 40168996
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.
Details
- Title: Subtitle
- Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria
- Creators
- Camila Marques-da-SilvaClyde Schmidt-SilvaCarson Bowers - University of GeorgiaNana Appiah Essel Charles-ChessCristina Samuel - University of GeorgiaJustine C ShiauEui-Soon ParkZhongyu YuanBae-Hoon KimDennis E KyleJohn T HartyJohn D MacMickingSamarchith P Kurup
- Resource Type
- Journal article
- Publication Details
- Cell host & microbe, Vol.33(4), pp.529-544.e9
- Publisher
- Elsevier
- DOI
- 10.1016/j.chom.2025.03.008
- PMID
- 40168996
- ISSN
- 1934-6069
- eISSN
- 1934-6069
- Grant note
- UGA CTEGD Flow Cytometry Core, UGA CTEGD Biomedical Microscopy Core - US National Institutes of Health: T32AI060546, AI153290, AI114543, AI167847, AI178159, AI185067, AI185725, AI068041-15, AI108834-10, AI168307 Howard Hughes Medical Institute
We would like to thank Drs. Fernando Sanchez-Valdez (UGA) , Drew Etheridge (UGA) , Rahul Vijay (RFU) , and Photini Sinnis (Johns Hopkins) for technicalassistance and the UGA CTEGD Flow Cytometry Core, UGA CTEGD Biomedical Microscopy Core, UGA CVM Cytometry Core facility, UGA CTEGD Sporocore, Yale Genome Editing Center and the UGA, and Yale animal research facility staff for their support. These studies were funded by the US National Institutes of Health (T32AI060546 to C.S.-S. and J.C.S.; AI153290 to D.E.K.; AI114543, AI167847, AI178159, AI185067, and AI185725 to J.T.H.; AI068041-15 and AI108834-10 to J.D.M.; and AI168307 to S.P.K.) . D.E.K. is a Georgia Research Alliance scholar. J.D.M. is an Investigator of the Howard Hughes Medical Institute.
- Language
- English
- Date published
- 04/09/2025
- Academic Unit
- Pathology
- Record Identifier
- 9984805009202771
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