Metabolic Adaptation to Tissue Iron Overload Confers Tolerance to Malaria

Gozzelino, Raffaella, Andrade, Bruno Bezerril, Larsen, Rasmus, Luz, Nivea F., Vanoaica, Liviu, Seixas, Elsa, Coutinho, Antonio, Cardoso, Silvia, Rebelo, Sofia, Poli, Maura, Barral-Netto, Manoel, Darshan, Deepak, Kuehn, Lukas C. and Soares, Miguel P. (2012) Metabolic Adaptation to Tissue Iron Overload Confers Tolerance to Malaria. Cell Host and Microbe, 12 5: 693-704. doi:10.1016/j.chom.2012.10.011

Author Gozzelino, Raffaella
Andrade, Bruno Bezerril
Larsen, Rasmus
Luz, Nivea F.
Vanoaica, Liviu
Seixas, Elsa
Coutinho, Antonio
Cardoso, Silvia
Rebelo, Sofia
Poli, Maura
Barral-Netto, Manoel
Darshan, Deepak
Kuehn, Lukas C.
Soares, Miguel P.
Title Metabolic Adaptation to Tissue Iron Overload Confers Tolerance to Malaria
Journal name Cell Host and Microbe   Check publisher's open access policy
ISSN 1931-3128
Publication date 2012-11-01
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.chom.2012.10.011
Open Access Status Not yet assessed
Volume 12
Issue 5
Start page 693
End page 704
Total pages 12
Place of publication Cambridge, MA United States
Publisher Cell Press
Language eng
Formatted abstract
Disease tolerance is a defense strategy that limits the fitness costs of infection irrespectively of pathogen burden. While restricting iron (Fe) availability to pathogens is perceived as a host defense strategy, the resulting tissue Fe overload can be cytotoxic and promote tissue damage to exacerbate disease severity. Examining this interplay during malaria, the disease caused by Plasmodium infection, we find that expression of the Fe sequestering protein ferritin H chain (FtH) in mice, and ferritin in humans, is associated with reduced tissue damage irrespectively of pathogen burden. FtH protection relies on its ferroxidase activity, which prevents labile Fe from sustaining proapoptotic c-Jun N-terminal kinase (JNK) activation. FtH expression is inhibited by JNK activation, promoting tissue Fe overload, tissue damage, and malaria severity. Mimicking FtH’s antioxidant effect or inhibiting JNK activation pharmacologically confers therapeutic tolerance to malaria in mice. Thus, FtH provides metabolic adaptation to tissue Fe overload, conferring tolerance to malaria. 
Keyword Alpha Induced Apoptosis
Necrosis factor alpha
Ferritin Heavy Chain
Induced Cell Death
Infectious Diseases
Oxidative Stress
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID PTDC/BIA-BCM/101311/2008
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 44 times in Thomson Reuters Web of Science Article | Citations
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