期刊
CELL HOST & MICROBE
卷 12, 期 5, 页码 693-704出版社
CELL PRESS
DOI: 10.1016/j.chom.2012.10.011
关键词
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资金
- Fundacao pars a Ciencia e Tecnologia (Portugal) [PTDC/BIA-BCM/101311/2008, PTDC/SAU-FCF/100762/2008, PTDC/SAU-TOX/116627/2010]
- European Community [LSH-2005-1.2.5-1, ERC-2011-AdG. 294709]
- Financiadora de Estudos e Projetos/Fundo Nacional de Desenvolvimento Cientifico e Tecnologico Amazonia, Brazil [010409605]
- Conselho Nacional de Pesquisa e Tecnologia (Brazil)
- intramural research program of the National Institute of Allergy and Infectious Diseases, NIH
- Fundação para a Ciência e a Tecnologia [PTDC/BIA-BCM/101311/2008, PTDC/SAU-FCF/100762/2008] Funding Source: FCT
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.
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