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Analysis of innate defences against Plasmodium falciparum in immunodeficient mice.

Arnold L, Tyagi RK, Mejia P, Van Rooijen N, Pérignon JL, Druilhe P - Malar. J. (2010)

Bottom Line: The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery.The innate responses towards the murine parasite Plasmodium yoelii were used as a control.Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, 28, rue du Dr Roux, 75015 Paris, France.

ABSTRACT

Background: Mice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed.

Methods: NOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control.

Results: Results show that 1) P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2) in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3) human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4) macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role.

Conclusions: Despite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

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P. yoelii is far less pro-inflammatory than P. falciparum. P. yoelii non lethal XNL 1.1 strain was injected i.p. in NOD/SCID mice and the same parameters as in P. falciparum infected mice were assessed (see the legend of figure 2). (A) Peripheral blood parasitaemia; (B) Total number of leukocyte per μl of blood (plain circle) at different time post-infection. The numbers of CD11b+ F4/80+ monocytes (black square, line dot) and CD11b+ Ly-6G+ PMN (white triangle) were calculated from the percentages obtained by FACS analysis. The percentage of CD43- CD62L+ Ly-6C+ inflammatory monocytes was also assessed by FACS (open circle, dotted line); (C) Cytokines/chemokine levels determined using the CBA mouse inflammatory cytokines kit. Results represent the means ± SEM from 2 distinct experiments (n = 5 mice).
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Figure 3: P. yoelii is far less pro-inflammatory than P. falciparum. P. yoelii non lethal XNL 1.1 strain was injected i.p. in NOD/SCID mice and the same parameters as in P. falciparum infected mice were assessed (see the legend of figure 2). (A) Peripheral blood parasitaemia; (B) Total number of leukocyte per μl of blood (plain circle) at different time post-infection. The numbers of CD11b+ F4/80+ monocytes (black square, line dot) and CD11b+ Ly-6G+ PMN (white triangle) were calculated from the percentages obtained by FACS analysis. The percentage of CD43- CD62L+ Ly-6C+ inflammatory monocytes was also assessed by FACS (open circle, dotted line); (C) Cytokines/chemokine levels determined using the CBA mouse inflammatory cytokines kit. Results represent the means ± SEM from 2 distinct experiments (n = 5 mice).

Mentions: Innate immune responses triggered by P. falciparum were compared with those elicited by the murine non-lethal parasite P. yoelii XNL 1.1 strain. In contrast to P. falciparum, P. yoelii induced an exponential increase in parasitaemia in immunodeficient NOD/SCID mice reaching more than 60% within two weeks (Figure 3A), accompanied by a major drop in haematocrit (52 to 18% by week 2), and ultimately led to the death of the animals. An increase in the numbers of circulating leukocytes occurred, but was delayed, until parasitaemia was already high (ca. 10%) (Figures 3A and 3B). The number of leukocytes increased 3.5 fold from day 7 (2600 ± 800 leukocytes/μl) to day 15 (9100 ± 2250) post-infection (P < 0.004). This was mainly due to a 4.2 fold increase in PMN from day 11 (1060 ± 630) to 15 (5500 ± 1300) (P < 0.008). There was a major, 7.1 fold, increase of NK cells from day 7 (95 ± 50 NK cells/μl) to day 15 (675 ± 180) (P < 0.001), and a lower, 2.2 fold, increase in MO from day 4 (560 ± 230 MO/μl) to 7 (1200 ± 390) (P < 0.013).


Analysis of innate defences against Plasmodium falciparum in immunodeficient mice.

Arnold L, Tyagi RK, Mejia P, Van Rooijen N, Pérignon JL, Druilhe P - Malar. J. (2010)

P. yoelii is far less pro-inflammatory than P. falciparum. P. yoelii non lethal XNL 1.1 strain was injected i.p. in NOD/SCID mice and the same parameters as in P. falciparum infected mice were assessed (see the legend of figure 2). (A) Peripheral blood parasitaemia; (B) Total number of leukocyte per μl of blood (plain circle) at different time post-infection. The numbers of CD11b+ F4/80+ monocytes (black square, line dot) and CD11b+ Ly-6G+ PMN (white triangle) were calculated from the percentages obtained by FACS analysis. The percentage of CD43- CD62L+ Ly-6C+ inflammatory monocytes was also assessed by FACS (open circle, dotted line); (C) Cytokines/chemokine levels determined using the CBA mouse inflammatory cytokines kit. Results represent the means ± SEM from 2 distinct experiments (n = 5 mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914061&req=5

Figure 3: P. yoelii is far less pro-inflammatory than P. falciparum. P. yoelii non lethal XNL 1.1 strain was injected i.p. in NOD/SCID mice and the same parameters as in P. falciparum infected mice were assessed (see the legend of figure 2). (A) Peripheral blood parasitaemia; (B) Total number of leukocyte per μl of blood (plain circle) at different time post-infection. The numbers of CD11b+ F4/80+ monocytes (black square, line dot) and CD11b+ Ly-6G+ PMN (white triangle) were calculated from the percentages obtained by FACS analysis. The percentage of CD43- CD62L+ Ly-6C+ inflammatory monocytes was also assessed by FACS (open circle, dotted line); (C) Cytokines/chemokine levels determined using the CBA mouse inflammatory cytokines kit. Results represent the means ± SEM from 2 distinct experiments (n = 5 mice).
Mentions: Innate immune responses triggered by P. falciparum were compared with those elicited by the murine non-lethal parasite P. yoelii XNL 1.1 strain. In contrast to P. falciparum, P. yoelii induced an exponential increase in parasitaemia in immunodeficient NOD/SCID mice reaching more than 60% within two weeks (Figure 3A), accompanied by a major drop in haematocrit (52 to 18% by week 2), and ultimately led to the death of the animals. An increase in the numbers of circulating leukocytes occurred, but was delayed, until parasitaemia was already high (ca. 10%) (Figures 3A and 3B). The number of leukocytes increased 3.5 fold from day 7 (2600 ± 800 leukocytes/μl) to day 15 (9100 ± 2250) post-infection (P < 0.004). This was mainly due to a 4.2 fold increase in PMN from day 11 (1060 ± 630) to 15 (5500 ± 1300) (P < 0.008). There was a major, 7.1 fold, increase of NK cells from day 7 (95 ± 50 NK cells/μl) to day 15 (675 ± 180) (P < 0.001), and a lower, 2.2 fold, increase in MO from day 4 (560 ± 230 MO/μl) to 7 (1200 ± 390) (P < 0.013).

Bottom Line: The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery.The innate responses towards the murine parasite Plasmodium yoelii were used as a control.Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, 28, rue du Dr Roux, 75015 Paris, France.

ABSTRACT

Background: Mice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed.

Methods: NOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control.

Results: Results show that 1) P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2) in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3) human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4) macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role.

Conclusions: Despite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

Show MeSH
Related in: MedlinePlus