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Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

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Iron Dextran Prevents the Development of ECM.Survival (a) and mean parasitemia (b) of infected mice treated with iron dextran, dextran Mw 5kDa and dextran Mw 70kDa. PBS-treated mice were used as a control. BBB disruption was assessed using Evans blue (EB). EB quantification (c) is shown as mean μg of EB per g of brain tissue normalized to mean μg of EB per g of heart tissue. Representative picture of EB-stained brains (d). For survival: n = 29 for control mice, n = 31 for FeD mice and n = 5 for Dex5 and Dex70 mice. The average of four individual experiments is shown for the control and FeD mice. For parasitemia: n = 20 for control and FeD mice and n = 5 for Dex5 and Dex70. The average of three individual experiments is shown for the control and FeD mice. For EB: n = 5 for control, uninfected and infected mice, and n = 6 for iron dextran-treated, uninfected and infected mice. PBS = control, Dex5 = dextran Mw 5kDa, Dex70 = dextran Mw 70kDa, FeD = iron dextran, UI = uninfected, I = infected. Statistically significant differences, shown by asterisks (* P < 0.05, ** P < 0.01, and *** P < 0.001), were determined by log-rank test (survival) and unpaired Student’s t-test (BBB disruption).
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pone.0118451.g001: Iron Dextran Prevents the Development of ECM.Survival (a) and mean parasitemia (b) of infected mice treated with iron dextran, dextran Mw 5kDa and dextran Mw 70kDa. PBS-treated mice were used as a control. BBB disruption was assessed using Evans blue (EB). EB quantification (c) is shown as mean μg of EB per g of brain tissue normalized to mean μg of EB per g of heart tissue. Representative picture of EB-stained brains (d). For survival: n = 29 for control mice, n = 31 for FeD mice and n = 5 for Dex5 and Dex70 mice. The average of four individual experiments is shown for the control and FeD mice. For parasitemia: n = 20 for control and FeD mice and n = 5 for Dex5 and Dex70. The average of three individual experiments is shown for the control and FeD mice. For EB: n = 5 for control, uninfected and infected mice, and n = 6 for iron dextran-treated, uninfected and infected mice. PBS = control, Dex5 = dextran Mw 5kDa, Dex70 = dextran Mw 70kDa, FeD = iron dextran, UI = uninfected, I = infected. Statistically significant differences, shown by asterisks (* P < 0.05, ** P < 0.01, and *** P < 0.001), were determined by log-rank test (survival) and unpaired Student’s t-test (BBB disruption).

Mentions: To determine the effect of parenteral iron supplementation on the pathology of ECM, we infected iron dextran-treated (FeD) mice with P. berghei ANKA. C57BL/6 mice infected with this parasite develop clinical symptoms of ECM (i.e., hemi- or paraplegia, convulsions and coma) and succumb to the disease within 6 to 9 d post-infection [26,27]. Dextran controls (with Mw = 5,000 kDa and 70,000 kDa) were included to establish if the dextran component itself was augmentative. PBS-treated (control) and dextran-treated mice developed ECM between days 7 and 11 post-infection, and their mortality was 100% (Fig. 1A). In contrast, FeD mice were markedly protected, with a mortality of only 0–20% (Fig. 1A). Additionally, further experiments revealed that iron supplementation provided a slight, but significant, protective effect when started up to 4 days post-infection (Figure A in S1 File). The level of parasitemia for control, dextran-treated and FeD mice was found to be similar through day 11 post-infection, by which time all control and dextran-treated mice had succumbed to ECM (Fig. 1B). This result suggests that the protective effect of iron dextran does not rely on the inhibition of parasitemia. FeD mice that did not develop ECM had increasing levels of parasitemia and either died due to the development of hyperparasitemia (pRBC > 80%) or were sacrificed on day 25 post-infection (Fig. 1B). Since the mice treated with the dextran controls had the same clinical phenotype as the control mice, the iron-mediated protection was further investigated using only the control mice. ECM incidence was confirmed by analyzing the integrity of the BBB, which is a hallmark of ECM pathology [6]. The uptake of Evans blue (EB) into the brain parenchyma, which is indicative of BBB disruption, was evident in the infected control mice and was significantly reduced in the FeD mice (Fig. 1C, D), indicating that iron supplementation prevented the loss of BBB integrity during ECM.


Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

Iron Dextran Prevents the Development of ECM.Survival (a) and mean parasitemia (b) of infected mice treated with iron dextran, dextran Mw 5kDa and dextran Mw 70kDa. PBS-treated mice were used as a control. BBB disruption was assessed using Evans blue (EB). EB quantification (c) is shown as mean μg of EB per g of brain tissue normalized to mean μg of EB per g of heart tissue. Representative picture of EB-stained brains (d). For survival: n = 29 for control mice, n = 31 for FeD mice and n = 5 for Dex5 and Dex70 mice. The average of four individual experiments is shown for the control and FeD mice. For parasitemia: n = 20 for control and FeD mice and n = 5 for Dex5 and Dex70. The average of three individual experiments is shown for the control and FeD mice. For EB: n = 5 for control, uninfected and infected mice, and n = 6 for iron dextran-treated, uninfected and infected mice. PBS = control, Dex5 = dextran Mw 5kDa, Dex70 = dextran Mw 70kDa, FeD = iron dextran, UI = uninfected, I = infected. Statistically significant differences, shown by asterisks (* P < 0.05, ** P < 0.01, and *** P < 0.001), were determined by log-rank test (survival) and unpaired Student’s t-test (BBB disruption).
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pone.0118451.g001: Iron Dextran Prevents the Development of ECM.Survival (a) and mean parasitemia (b) of infected mice treated with iron dextran, dextran Mw 5kDa and dextran Mw 70kDa. PBS-treated mice were used as a control. BBB disruption was assessed using Evans blue (EB). EB quantification (c) is shown as mean μg of EB per g of brain tissue normalized to mean μg of EB per g of heart tissue. Representative picture of EB-stained brains (d). For survival: n = 29 for control mice, n = 31 for FeD mice and n = 5 for Dex5 and Dex70 mice. The average of four individual experiments is shown for the control and FeD mice. For parasitemia: n = 20 for control and FeD mice and n = 5 for Dex5 and Dex70. The average of three individual experiments is shown for the control and FeD mice. For EB: n = 5 for control, uninfected and infected mice, and n = 6 for iron dextran-treated, uninfected and infected mice. PBS = control, Dex5 = dextran Mw 5kDa, Dex70 = dextran Mw 70kDa, FeD = iron dextran, UI = uninfected, I = infected. Statistically significant differences, shown by asterisks (* P < 0.05, ** P < 0.01, and *** P < 0.001), were determined by log-rank test (survival) and unpaired Student’s t-test (BBB disruption).
Mentions: To determine the effect of parenteral iron supplementation on the pathology of ECM, we infected iron dextran-treated (FeD) mice with P. berghei ANKA. C57BL/6 mice infected with this parasite develop clinical symptoms of ECM (i.e., hemi- or paraplegia, convulsions and coma) and succumb to the disease within 6 to 9 d post-infection [26,27]. Dextran controls (with Mw = 5,000 kDa and 70,000 kDa) were included to establish if the dextran component itself was augmentative. PBS-treated (control) and dextran-treated mice developed ECM between days 7 and 11 post-infection, and their mortality was 100% (Fig. 1A). In contrast, FeD mice were markedly protected, with a mortality of only 0–20% (Fig. 1A). Additionally, further experiments revealed that iron supplementation provided a slight, but significant, protective effect when started up to 4 days post-infection (Figure A in S1 File). The level of parasitemia for control, dextran-treated and FeD mice was found to be similar through day 11 post-infection, by which time all control and dextran-treated mice had succumbed to ECM (Fig. 1B). This result suggests that the protective effect of iron dextran does not rely on the inhibition of parasitemia. FeD mice that did not develop ECM had increasing levels of parasitemia and either died due to the development of hyperparasitemia (pRBC > 80%) or were sacrificed on day 25 post-infection (Fig. 1B). Since the mice treated with the dextran controls had the same clinical phenotype as the control mice, the iron-mediated protection was further investigated using only the control mice. ECM incidence was confirmed by analyzing the integrity of the BBB, which is a hallmark of ECM pathology [6]. The uptake of Evans blue (EB) into the brain parenchyma, which is indicative of BBB disruption, was evident in the infected control mice and was significantly reduced in the FeD mice (Fig. 1C, D), indicating that iron supplementation prevented the loss of BBB integrity during ECM.

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

Show MeSH
Related in: MedlinePlus