PMID- 23159058
OWN - NLM
STAT- MEDLINE
DCOM- 20130515
LR  - 20220408
IS  - 1934-6069 (Electronic)
IS  - 1931-3128 (Linking)
VI  - 12
IP  - 5
DP  - 2012 Nov 15
TI  - Metabolic adaptation to tissue iron overload confers tolerance to malaria.
PG  - 693-704
LID - S1931-3128(12)00357-5 [pii]
LID - 10.1016/j.chom.2012.10.011 [doi]
AB  - 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.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Gozzelino, Raffaella
AU  - Gozzelino R
AD  - Instituto Gulbenkian de Ciencia, 2780-156 Oeiras, Portugal.
FAU - Andrade, Bruno Bezerril
AU  - Andrade BB
FAU - Larsen, Rasmus
AU  - Larsen R
FAU - Luz, Nivea F
AU  - Luz NF
FAU - Vanoaica, Liviu
AU  - Vanoaica L
FAU - Seixas, Elsa
AU  - Seixas E
FAU - Coutinho, Antonio
AU  - Coutinho A
FAU - Cardoso, Silvia
AU  - Cardoso S
FAU - Rebelo, Sofia
AU  - Rebelo S
FAU - Poli, Maura
AU  - Poli M
FAU - Barral-Netto, Manoel
AU  - Barral-Netto M
FAU - Darshan, Deepak
AU  - Darshan D
FAU - Kuhn, Lukas C
AU  - Kuhn LC
FAU - Soares, Miguel P
AU  - Soares MP
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Host Microbe
JT  - Cell host & microbe
JID - 101302316
RN  - 0 (Antioxidants)
RN  - 9007-73-2 (Ferritins)
RN  - 9013-31-4 (Apoferritins)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.16.3.1 (Ceruloplasmin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Antioxidants/metabolism
MH  - Apoferritins/*metabolism
MH  - Cells, Cultured
MH  - Ceruloplasmin/metabolism
MH  - Cytoprotection
MH  - Enzyme Activation
MH  - Ferritins/*metabolism
MH  - Hepatocytes/metabolism
MH  - Host-Parasite Interactions
MH  - Humans
MH  - Iron/metabolism
MH  - Iron Overload/*metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Malaria/*metabolism/*parasitology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Plasmodium berghei/physiology
MH  - Plasmodium chabaudi/*immunology/*physiology
MH  - Plasmodium vivax/physiology
EDAT- 2012/11/20 06:00
MHDA- 2013/05/17 06:00
CRDT- 2012/11/20 06:00
PHST- 2012/04/20 00:00 [received]
PHST- 2012/08/28 00:00 [revised]
PHST- 2012/10/08 00:00 [accepted]
PHST- 2012/11/20 06:00 [entrez]
PHST- 2012/11/20 06:00 [pubmed]
PHST- 2013/05/17 06:00 [medline]
AID - S1931-3128(12)00357-5 [pii]
AID - 10.1016/j.chom.2012.10.011 [doi]
PST - ppublish
SO  - Cell Host Microbe. 2012 Nov 15;12(5):693-704. doi: 10.1016/j.chom.2012.10.011.