Ferroptosis-like signaling facilitates a potent innate defense against Plasmodium infection

The facets of host control during Plasmodium liver infection remain largely unknown and conventional innate regulatory pathways are only minimally effective at eliminating parasites. Ferroptosis, a recently described form of iron-dependent cell death that drives accumulation of reactive oxygen speci...

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Bibliographic Details
Published inbioRxiv
Main Authors Kain, Heather S, Arang, Nadia, Glennon, Elizabeth, Douglass, Alyse N, Dudgeon, Denali R, Johnson, Jarrod S, Aderem, Alan, Kaushansky, Alexis
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 31.01.2018
Subjects
Cell death
Ferroptosis
Hepatocytes
Immune response
Infections
Innate immunity
Liver
p53 Protein
Parasites
Reactive oxygen species
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Summary:The facets of host control during Plasmodium liver infection remain largely unknown and conventional innate regulatory pathways are only minimally effective at eliminating parasites. Ferroptosis, a recently described form of iron-dependent cell death that drives accumulation of reactive oxygen species and lipid peroxides, but has not yet been shown to function as an innate immune response. Inducing ferroptosis with pharmacologicals or by genetic perturbation of its negative regulators, GPX4 and SLC7a11, dramatically reduces survival of the Plasmodium Liver Stage. In contrast, knockdown or knockout of NOX1 or knockdown of TFR1, which are required for ferroptosis, increases the number of Liver Stage parasites. Moreover, we demonstrate that blocking ferroptosis renders parasite-infected hepatocytes resistant to P53 mediated hepatocyte death. Our work establishes that ferroptotic signaling serves to control Plasmodium infection in the liver and raises the possibility that ferroptosis operates as an axis of the innate immune system to defend against intracellular pathogens.
DOI:10.1101/257287