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.

Tissue damage control in disease tolerance

“…The same rationale can be applied to the treatment of non-communicable diseases in which inflammation and/or immunity act as the underlying cause of disease. In support of this notion, pharmacologic use of antioxidants confers disease tolerance to Plasmodium infection in mice 86,87 . Also, activation of DNA damage responses and autophagy by anthracyclines -involving ATM, LC3B, ATG7 -confers disease tolerance to polymicrobial infections, acting therapeutically against severe sepsis in mice 62 .…”

“…In the specific context of Plasmodium infection 93 these have been linked functionally to a evolutionary conserved stress-responsive and cytoprotective program that provides metabolic adaptation to cellular iron overload 87,95 . Two effector genes have been functionally implicated, namely the heme catabolizing enzyme HO-1 86,96,97 and the ferritin heart/heavy chain (FTH) 87,95 .…”

“…Moreover, systemic disruption of cellular iron export can interrupt iron supply to hemoglobin synthesis and erythropoiesis, causing anemia of chronic disease 106 . Therefore systemic modulation of host iron metabolism during infection provides a paradigm for the requirement of an integrated host defense strategy in which resistance mechanisms must be coupled to tissue damage control as to limit the severity of infectious diseases 87,95 . This is accomplished via metabolic adaptation to tissue iron overload, via a mechanism involving the expression of ferritins 87,95 .…”

“…FTH ferroxidase activity converts reactive iron (Fe 2+ ) into inert iron (Fe 3+ ) that does not partake in the production of free radicals via the Fenton chemistry 95 . This anti-oxidant effect confers tissue damage control and disease tolerance to infection in mammals 87,95 as well as in plants 108 , arguing for the evolutionarily conserved nature of this host defense strategy.…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The infection by Plasmodium was associated with the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK), that, in turns, inhibited ferritin expression and promoted tissue iron overload and damage. When FtH (in mice) or ferritin (in humans) was over-expressed, it sequestered free iron and attenuated ROS production and JNK induction; this led to limitation of tissue damage, regardless of iron overload and pathogen burden (Gozzelino et al 2012). …”