title: Metabolic adaptation to tissue iron overload confers tolerance to malaria.
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.
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gozzelino
authors.forename: Bruno Bezerril
authors.initials: BB
authors.lastname: Andrade
authors.forename: Rasmus
authors.initials: R
authors.lastname: Larsen
authors.forename: Nivea F
authors.initials: NF
authors.lastname: Luz
authors.forename: Liviu
authors.initials: L
authors.lastname: Vanoaica
authors.forename: Elsa
authors.initials: E
authors.lastname: Seixas
authors.forename: Antonio
authors.initials: A
authors.lastname: Coutinho
authors.forename: Sílvia
authors.initials: S
authors.lastname: Cardoso
authors.forename: Sofia
authors.initials: S
authors.lastname: Rebelo
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
authors.forename: Deepak
authors.initials: D
authors.lastname: Darshan
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Kühn
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001052:Apoferritins / Q000378:metabolism*; D002478:Cells, Cultured; D002570:Ceruloplasmin / Q000378:metabolism; D019610:Cytoprotection; D004789:Enzyme Activation; D005293:Ferritins / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008288:Malaria / Q000378:metabolism* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000502:physiology; D016788:Plasmodium chabaudi / Q000276:immunology* / Q000502:physiology*; D010966:Plasmodium vivax / Q000502:physiology
chemical_list: D000975:Antioxidants; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; D002570:Ceruloplasmin; D048031:JNK Mitogen-Activated Protein Kinases