Metabolic adaptation to tissue iron overload confers tolerance to malaria

Inducing ferritin H chain expression in host tissues makes hosts tolerant to malaria via iron sequestration, ferroxidase activity, and reduced oxidative damage through JNK signaling modulation.

“For example, induction of ferritin H chain (FtH) expression in host tissues confers tolerance to malaria through FtH-mediated iron sequestration, ferroxidase activity, and inhibition of oxidative damage by modulation of JNK signaling (Gozzelino et al., 2012).”

Heme catabolism and subsequent intracellular iron storage by ferritin confers host protection against the blood stage of Plasmodium infection while increasing susceptibility to intracellular Salmonella.

“For example, heme catabolism by and subsequent intracellular Fe storage by ferritin [54,107] confers host protection against the blood stage of Plasmodium infection while increasing susceptibility to the intracellular bacteria Salmonella [108].”

Heme sensitizes cells to undergo apoptosis, as indicated by partial suppression of heme sensitization by caspase inhibition.

“Heme sensitization to programmed cell death is partially suppressed by pharmacologic inhibition of caspases [106,107], indicating that heme sensitizes cells to undergo apoptosis [216].”

Once released from hemoglobin, labile heme becomes pro-oxidant and cytotoxic.

“Once released from hemoglobin, the redox activity of labile heme becomes pro-oxidant and cytotoxic [38,106,107,190] (Fig 4).”

Heme-mediated cytotoxicity involves sustained activation of the JNK signaling pathway.

“The mechanism underlying heme-mediated cytotoxicity involves the sustained activation of the c-Jun N-terminal kinase (JNK) signaling transduction pathway [107] (Fig 4).”

This pro-oxidant effect blunts redox-sensitive phosphatases controlling JNK activation, inducing programmed cell death in response to TNF.

“This pro-oxidant effect blunts the activity of redoxsensitive phosphatases controlling JNK activation [213,214], thus inducing programmed cell death in response to TNF [107,213,215].”

Mice with Fth deletion develop tissue Fe overload and tissue damage and succumb to Plasmodium and polymicrobial infections.

“Mice in which the Fth allele is deleted develop tissue Fe overload and tissue damage succumbing to Plasmodium [107] as well as to polymicrobial infections (unpublished observation).”

In systemic infections, the protective effects of HO-1 are assisted by FTH.

“In the context of systemic infections, the protective effects exerted by HO-1 are assisted by FTH [54,107] (Fig 4).”

Ferritin induction is essential for host survival of extracellular bacterial infections and Plasmodium infection.

“Induction of ferritin expression is essential to sustain host survival of extracellular bacterial infections (52) as well as Plasmodium infection (53).”