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Metabolic adaptation to tissue iron overload confers tolerance to malaria

Raffaella Gozzelino1, Bruno Bezerril Andrade, Rasmus Larsen

  • 1Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.

Cell Host & Microbe
|November 20, 2012
PubMed

Insights

Disease tolerance limits infection costs. Ferritin H chain (FtH) reduces malaria-related tissue damage by preventing iron overload and JNK activation, offering a therapeutic target for malaria.

Area of Science:

  • Biochemistry
  • Immunology
  • Pathology

Background:

  • Disease tolerance mitigates infection's fitness costs without eliminating pathogens.
  • Host iron sequestration can paradoxically increase tissue damage due to iron overload.
  • Malaria pathogenesis involves complex host-pathogen interactions and iron metabolism.

Purpose of the Study:

  • To investigate the role of ferritin H chain (FtH) in modulating tissue damage during malaria.
  • To elucidate the mechanism by which FtH influences iron overload and host cell apoptosis.
  • To explore therapeutic strategies targeting iron metabolism for malaria tolerance.

Main Methods:

  • Studied FtH expression in mouse models of malaria.
  • Assessed the impact of FtH ferroxidase activity on iron levels and JNK signaling.
  • Investigated the effects of mimicking FtH's antioxidant properties and inhibiting JNK pharmacologically.

Main Results:

  • FtH expression correlated with reduced tissue damage in malaria, independent of parasite load.
  • FtH's protective effect is mediated by its ferroxidase activity, inhibiting pro-apoptotic JNK activation.
  • JNK activation suppresses FtH, leading to iron overload and exacerbated malaria severity.
  • Pharmacological interventions mimicking FtH's antioxidant effects or inhibiting JNK conferred therapeutic tolerance.

Conclusions:

  • Ferritin H chain (FtH) confers metabolic adaptation to iron overload, promoting disease tolerance in malaria.
  • Targeting iron metabolism and JNK signaling presents a viable therapeutic strategy for malaria.
  • Understanding iron's dual role in infection is crucial for developing effective treatments.

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