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

Camila Marques-da-Silva; Clyde Schmidt-Silva; Carson Bowers; Nana Appiah; Essel Charles-Chess; Justine C Shiau; Eui-Soon Park; Zhongyu Yuan; Bae-Hoon Kim; Dennis E Kyle; John T Harty; John D MacMicking; Samarchith P Kurup

doi:10.1093/jimmun/vkaf283.131

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

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

Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Nana Appiah, Essel Charles-Chess, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, …

The Journal of immunology (1950), Vol.214(Supplement_1), vkaf283131

11/01/2025

DOI: 10.1093/jimmun/vkaf283.131

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Abstract

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)

Animals - Rodent Infections - Parasitic-Helminth Processes - Inflammation Techniques/Approaches - Molecular Biology Transgenic/Knockout Mice

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Title: Subtitle: Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria 2178
Creators: Camila Marques-da-Silva
Clyde Schmidt-Silva
Carson Bowers
Nana Appiah
Essel Charles-Chess
Justine C Shiau
Eui-Soon Park
Zhongyu Yuan
Bae-Hoon Kim
Dennis E Kyle
John T Harty
John D MacMicking
Samarchith P Kurup
Resource Type: Abstract
Publication Details: The Journal of immunology (1950), Vol.214(Supplement_1), vkaf283131
DOI: 10.1093/jimmun/vkaf283.131
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: Oxford University Press
Grant note: NIH/NIAID HHMI
NIH/NIAID HHMI
Alternative title: IMMUNOLOGY2025™ Abstracts
Language: English
Date published: 11/01/2025
Academic Unit: Pathology
Record Identifier: 9985034937102771

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