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Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

Bao LQ, Nhi DM, Huy NT, Kikuchi M, Yanagi T, Hamano S, Hirayama K - Malar. J. (2015)

Bottom Line: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells.The spleens of infected semi-immune mice were collected for flow cytometry analysis.CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. lamquocbao@nagasaki-u.ac.jp.

ABSTRACT

Background: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection.

Methods: C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia.

Results: The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts.

Conclusion: CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

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Related in: MedlinePlus

Splenic CD11c(+) cells from semi-immune mice lowered parasitaemia, enhanced anti-P. bergheiIgG1 level and improved the ECM survival rate in recipient mice. (A) Plots show the representative purity of CD11c(+) cells. (B) Survival curves for mice that received 106 splenic CD11c(+) cells and for PBS-treated control mice (n = 16-18 mice/group). Data shown are pooled from three independent experiments. Significant differences between groups as determined by log-rank test are indicated by symbols: *P < 0.05 for SI11c vs Na11c; $P < 0.05 for SI11c vs PBS. (C) Bar chart showing the median parasitaemia (%) of recipient mice over the time of infection (n = 6-9 mice/group). Parasitaemia (%) of these groups of mice was performed on days post challenge as indicated and was shown by the box-plots. Data shown are representative of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, Mann–Whitney U test. (D) Median levels of plasma anti-P. berghei IgG1, IgG2a and IgG2b were determined on day 5 post-infection in mice with adoptively transferred DCs. Data are representative of two separate experiments (n = 4 mice/group). *P < 0.05, Mann–Whitney U test.
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Fig2: Splenic CD11c(+) cells from semi-immune mice lowered parasitaemia, enhanced anti-P. bergheiIgG1 level and improved the ECM survival rate in recipient mice. (A) Plots show the representative purity of CD11c(+) cells. (B) Survival curves for mice that received 106 splenic CD11c(+) cells and for PBS-treated control mice (n = 16-18 mice/group). Data shown are pooled from three independent experiments. Significant differences between groups as determined by log-rank test are indicated by symbols: *P < 0.05 for SI11c vs Na11c; $P < 0.05 for SI11c vs PBS. (C) Bar chart showing the median parasitaemia (%) of recipient mice over the time of infection (n = 6-9 mice/group). Parasitaemia (%) of these groups of mice was performed on days post challenge as indicated and was shown by the box-plots. Data shown are representative of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, Mann–Whitney U test. (D) Median levels of plasma anti-P. berghei IgG1, IgG2a and IgG2b were determined on day 5 post-infection in mice with adoptively transferred DCs. Data are representative of two separate experiments (n = 4 mice/group). *P < 0.05, Mann–Whitney U test.

Mentions: To examine the long-lasting anti-malaria role of splenic CD11c(+) DCs derived from semi-immune mice, CD11c(+) cells was isolated with the purity >95% (Figure 2A) from the spleens of semi-immune mice three to four months after the third cured infection, as well as from age-matched naïve controls and passively transferred these cells to eight-weeks-old naïve mice. As shown in Figure 2B, 61% of mice receiving CD11c(+) cells from semi-immune mice (SI11c) were resistant to ECM and survived for 14 days post-infection. Finally, all of these mice succumbed to severe anemia and high parasitaemia around days 28–30 post-infection. Conversely, the survival rates of PBS-treated control mice and mice that received CD11c(+) cells from age-matched naïve mice (Na11c) were significantly lower during the first two weeks of infection, at 28 and 31%, respectively (P <0.05). Splenic CD11c(+) DCs from semi-immune mice with last immunization three months previously partially protected naïve B6 mice against ECM in the passive transfer experiments, confirming the beneficial effects of CD11c(+) DCs in prolonged protection against pathology. CD11c(+) cells from semi-immune mice had a noticeable attenuating effect on parasitaemia in recipients beginning on day 5 post-infection compared with PBS-treated control mice and those that received CD11c(+) cells from naïve mice (Figure 2C). It is known that in malaria infection, DCs containing RBCs expressed higher type I interferon[IFN] levels than those without RBCs [21]. Donor CD11c(+) DCs from semi-immune mice, including RBC containing DCs, probably extendedly produced more type I IFN than naïve DCs and then suppressed the parasite proliferation. Consequently, DCs could be one of effective cells for low parasitaemia which was previously observed in semi-immune mice [17]. Prevention of ECM through a lowering of parasitaemia correlated with reduced levels of pathogenic cytokines, chemokines, CD8(+) T cells, and parasites in the brain has been reported [29-31]. Hence, in the present study, the decrease in parasitaemia mediated by semi-immune DCs probably contributed to the improved survival rate of recipient mice during the acute phase of malaria. CD11c(+) DCs, major innate immune cells, are important in the development of immunity to malaria. Previous studies in mice have demonstrated that in malarial infections that prove lethal, the function of DCs is compromised, but functional DCs improve the survival rate in non-lethal malaria [23,32-35].Figure 2


Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

Bao LQ, Nhi DM, Huy NT, Kikuchi M, Yanagi T, Hamano S, Hirayama K - Malar. J. (2015)

Splenic CD11c(+) cells from semi-immune mice lowered parasitaemia, enhanced anti-P. bergheiIgG1 level and improved the ECM survival rate in recipient mice. (A) Plots show the representative purity of CD11c(+) cells. (B) Survival curves for mice that received 106 splenic CD11c(+) cells and for PBS-treated control mice (n = 16-18 mice/group). Data shown are pooled from three independent experiments. Significant differences between groups as determined by log-rank test are indicated by symbols: *P < 0.05 for SI11c vs Na11c; $P < 0.05 for SI11c vs PBS. (C) Bar chart showing the median parasitaemia (%) of recipient mice over the time of infection (n = 6-9 mice/group). Parasitaemia (%) of these groups of mice was performed on days post challenge as indicated and was shown by the box-plots. Data shown are representative of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, Mann–Whitney U test. (D) Median levels of plasma anti-P. berghei IgG1, IgG2a and IgG2b were determined on day 5 post-infection in mice with adoptively transferred DCs. Data are representative of two separate experiments (n = 4 mice/group). *P < 0.05, Mann–Whitney U test.
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Related In: Results  -  Collection

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Fig2: Splenic CD11c(+) cells from semi-immune mice lowered parasitaemia, enhanced anti-P. bergheiIgG1 level and improved the ECM survival rate in recipient mice. (A) Plots show the representative purity of CD11c(+) cells. (B) Survival curves for mice that received 106 splenic CD11c(+) cells and for PBS-treated control mice (n = 16-18 mice/group). Data shown are pooled from three independent experiments. Significant differences between groups as determined by log-rank test are indicated by symbols: *P < 0.05 for SI11c vs Na11c; $P < 0.05 for SI11c vs PBS. (C) Bar chart showing the median parasitaemia (%) of recipient mice over the time of infection (n = 6-9 mice/group). Parasitaemia (%) of these groups of mice was performed on days post challenge as indicated and was shown by the box-plots. Data shown are representative of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001, Mann–Whitney U test. (D) Median levels of plasma anti-P. berghei IgG1, IgG2a and IgG2b were determined on day 5 post-infection in mice with adoptively transferred DCs. Data are representative of two separate experiments (n = 4 mice/group). *P < 0.05, Mann–Whitney U test.
Mentions: To examine the long-lasting anti-malaria role of splenic CD11c(+) DCs derived from semi-immune mice, CD11c(+) cells was isolated with the purity >95% (Figure 2A) from the spleens of semi-immune mice three to four months after the third cured infection, as well as from age-matched naïve controls and passively transferred these cells to eight-weeks-old naïve mice. As shown in Figure 2B, 61% of mice receiving CD11c(+) cells from semi-immune mice (SI11c) were resistant to ECM and survived for 14 days post-infection. Finally, all of these mice succumbed to severe anemia and high parasitaemia around days 28–30 post-infection. Conversely, the survival rates of PBS-treated control mice and mice that received CD11c(+) cells from age-matched naïve mice (Na11c) were significantly lower during the first two weeks of infection, at 28 and 31%, respectively (P <0.05). Splenic CD11c(+) DCs from semi-immune mice with last immunization three months previously partially protected naïve B6 mice against ECM in the passive transfer experiments, confirming the beneficial effects of CD11c(+) DCs in prolonged protection against pathology. CD11c(+) cells from semi-immune mice had a noticeable attenuating effect on parasitaemia in recipients beginning on day 5 post-infection compared with PBS-treated control mice and those that received CD11c(+) cells from naïve mice (Figure 2C). It is known that in malaria infection, DCs containing RBCs expressed higher type I interferon[IFN] levels than those without RBCs [21]. Donor CD11c(+) DCs from semi-immune mice, including RBC containing DCs, probably extendedly produced more type I IFN than naïve DCs and then suppressed the parasite proliferation. Consequently, DCs could be one of effective cells for low parasitaemia which was previously observed in semi-immune mice [17]. Prevention of ECM through a lowering of parasitaemia correlated with reduced levels of pathogenic cytokines, chemokines, CD8(+) T cells, and parasites in the brain has been reported [29-31]. Hence, in the present study, the decrease in parasitaemia mediated by semi-immune DCs probably contributed to the improved survival rate of recipient mice during the acute phase of malaria. CD11c(+) DCs, major innate immune cells, are important in the development of immunity to malaria. Previous studies in mice have demonstrated that in malarial infections that prove lethal, the function of DCs is compromised, but functional DCs improve the survival rate in non-lethal malaria [23,32-35].Figure 2

Bottom Line: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells.The spleens of infected semi-immune mice were collected for flow cytometry analysis.CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. lamquocbao@nagasaki-u.ac.jp.

ABSTRACT

Background: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection.

Methods: C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia.

Results: The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts.

Conclusion: CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

Show MeSH
Related in: MedlinePlus