Role of iron in Trypanosoma cruzi infection of mice.

Abstract

As bstract. The role of iron in experimental infection of mice with Trypanosoma cruzi was investigated. B6 mice had a transient parasitemia and a transient anemia, both of maximal intensity 28 d after the inoculation of T. cruzi. There was a biphasic hypoferremic host response to infection with T. cruzi with the peak hypoferremia also occurring 28 d after inoculation ofthe parasite. The mortality rate from infection was increased from 23% in phosphate-buffered saline-treated B6 mice to 50% in a group of B6 mice receiving iron-dextran (P < 0.025), whereas depletion of iron stores with the iron chelator desferrioxamine B and an iron-deficient diet provided complete protection of B6 mice (P < 0.05). The mortality rate in the highly susceptible C3H strain was reduced from 100% in the control group to 45% (P . 0.025) in the iron-depleted group. The tissue iron stores were altered in mice receiving either iron-dextran or desferrioxamine B and an iron-deficient diet. In vitro, T. cruzi was shown to require both a heme and a nonheme iron source for an optimal growth rate. The effects of iron excess or depletion on the outcome of infection with T. cruzi correlated both with the growth requirements of the parasite for iron and with the availability of intracellular iron. Thus, it was suggested that the hypoferremic response, by sequestering iron within intracellular stores, potentially enhanced the pathogenicity of the intracellular parasites. Furthermore, the in vivo effects of iron excess and depletion correlated with an effect of iron on the growth rate and pathogenicity of the parasite. Dr. Lalonde was also supported by a fellowship from the Medical Research Council of Canada during part of the study period.

Oxidative stress fuels Trypanosoma cruzi infection in mice

“…cruzi amastigotes require iron to grow in axenic cultures (57). Chelating iron reduces T. cruzi infection in macrophages (58) and mice (59), while iron-rich diets or iron-dextran worsen infection (60), suggesting that iron is critical for T. cruzi growth. Here, we found that several strategies to increase the labile iron pool resulted in increased parasitism, while incubation of infected macrophages with Fe 2+ reversed the decrease in parasitism mediated by CoPP and other antioxidants.…”

Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis.

“…Furthermore, T. cruzi-infected mice fed iron dextran to increase intracellular iron stores have an increased mortality rate. Conversely, depletion of host iron stores with desferroxamine and an iron-deficient diet reduce the pathogenicity of infection with T. cruzi (46).…”

Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.

“…The synthesis of these cytokines is increased in a variety of infectious and noninfectious states, and these cytokines are felt to play a role in the hypoferremia seen in sepsis and chronic disease (35)(36)(37)(38). In the host infected with certain intracellular pathogens, this effect of IL-1 and TNF-increasing mononuclear phagocyte iron and ferritin may be detrimental (39). IFNy, a cytokine more specific to the cell-mediated immune response against intracellular pathogens, may play an important role in counteracting the influence of IL-1 and TNF on iron metabolism in mononuclear phagocytes.…”