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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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Tissue parasite sequestration is inhibited by parenteral iron supplementation.Parasite levels in the brain (a), spleen (b) and liver (c) on day 7 post-infection. Luciferase activity is shown as the total RLU per organ normalized to the total RLU in the control mice before symptoms. n = 8 for the control mice before symptoms, n = 8 for the control, symptomatic mice and n = 12 for the FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (** P < 0.01 and *** P < 0.001), were determined by unpaired Student’s t-test.
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pone.0118451.g002: Tissue parasite sequestration is inhibited by parenteral iron supplementation.Parasite levels in the brain (a), spleen (b) and liver (c) on day 7 post-infection. Luciferase activity is shown as the total RLU per organ normalized to the total RLU in the control mice before symptoms. n = 8 for the control mice before symptoms, n = 8 for the control, symptomatic mice and n = 12 for the FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (** P < 0.01 and *** P < 0.001), were determined by unpaired Student’s t-test.

Mentions: Recent studies have shown that a rapid increase in tissue parasite burden, independent of parasitemia, is associated with the induction of clinical ECM [28–32]. Parasite burden in the brain, spleen and liver were measured on day 7 post-infection using luciferase activity. Levels of parasitemia assessed using luciferase activity were similar to parasitemia as measured by counting blood smears, indicating that the two methods are comparable (Figure B.A in S1 File). Although a significant difference in the parasitemia between the control and FeD mice was not observed before the development of symptoms in the control mice, a marked increase in tissue parasite burden was observed in the control mice upon the development of clinical symptoms (Fig. 2A-C). An abrupt increase in the tissue parasite levels was not observed in FeD mice, as they did not become symptomatic. Since the tissue parasite burden in the control mice only increased upon the development of symptoms, the surge in parasites is likely associated with the onset of ECM pathology, which is in agreement with previous studies [28–32]. In the control mice the parasite burden increased to a greater extent in the brain compared to the spleen and the liver. However, parasite sequestration in the infected FeD mice and the infected control mice before the development of symptoms (as measured by the ratio of the relative luminescence units (RLU) of the infected FeD mice or the infected control before the development of symptoms to the RLU of the uninfected mice) was much more extensive in the spleen (2250 fold increase) and liver (40 fold increase) than in the brain (3 fold increase) (Figure B.B-D in S1 File). This large variance may account for the apparent lack of parasite sequestration detected in the brain of infected mice in some earlier studies [33].


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)

Tissue parasite sequestration is inhibited by parenteral iron supplementation.Parasite levels in the brain (a), spleen (b) and liver (c) on day 7 post-infection. Luciferase activity is shown as the total RLU per organ normalized to the total RLU in the control mice before symptoms. n = 8 for the control mice before symptoms, n = 8 for the control, symptomatic mice and n = 12 for the FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (** P < 0.01 and *** P < 0.001), were determined by unpaired Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359107&req=5

pone.0118451.g002: Tissue parasite sequestration is inhibited by parenteral iron supplementation.Parasite levels in the brain (a), spleen (b) and liver (c) on day 7 post-infection. Luciferase activity is shown as the total RLU per organ normalized to the total RLU in the control mice before symptoms. n = 8 for the control mice before symptoms, n = 8 for the control, symptomatic mice and n = 12 for the FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (** P < 0.01 and *** P < 0.001), were determined by unpaired Student’s t-test.
Mentions: Recent studies have shown that a rapid increase in tissue parasite burden, independent of parasitemia, is associated with the induction of clinical ECM [28–32]. Parasite burden in the brain, spleen and liver were measured on day 7 post-infection using luciferase activity. Levels of parasitemia assessed using luciferase activity were similar to parasitemia as measured by counting blood smears, indicating that the two methods are comparable (Figure B.A in S1 File). Although a significant difference in the parasitemia between the control and FeD mice was not observed before the development of symptoms in the control mice, a marked increase in tissue parasite burden was observed in the control mice upon the development of clinical symptoms (Fig. 2A-C). An abrupt increase in the tissue parasite levels was not observed in FeD mice, as they did not become symptomatic. Since the tissue parasite burden in the control mice only increased upon the development of symptoms, the surge in parasites is likely associated with the onset of ECM pathology, which is in agreement with previous studies [28–32]. In the control mice the parasite burden increased to a greater extent in the brain compared to the spleen and the liver. However, parasite sequestration in the infected FeD mice and the infected control mice before the development of symptoms (as measured by the ratio of the relative luminescence units (RLU) of the infected FeD mice or the infected control before the development of symptoms to the RLU of the uninfected mice) was much more extensive in the spleen (2250 fold increase) and liver (40 fold increase) than in the brain (3 fold increase) (Figure B.B-D in S1 File). This large variance may account for the apparent lack of parasite sequestration detected in the brain of infected mice in some earlier studies [33].

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