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Mechanisms controlling anaemia in Trypanosoma congolense infected mice.

Noyes HA, Alimohammadian MH, Agaba M, Brass A, Fuchs H, Gailus-Durner V, Hulme H, Iraqi F, Kemp S, Rathkolb B, Wolf E, de Angelis MH, Roshandel D, Naessens J - PLoS ONE (2009)

Bottom Line: Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia.However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng.The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.

ABSTRACT

Background: Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia.

Methodology/principal findings: The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng.

Conclusions/significance: The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection.

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(A) Mean weights of internal organs relative to body weight during T. congolense infection in A/J mice (red), BALB/c mice (blue) and C57BL/6 (green) mice, shown as mean±SD. The mean relative weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold over the course of the infection (p<0.001). There were statistically significant (ANOVA p<0.05) differences in weight between strains at most time points but the largest and perhaps biologically most significant difference was in the spleen where the relative weight in BALB/c mice increased 12 fold and in A/J and C57BL/6 mice it increased about 9.4 fold. (B) The increase in mean spleen and liver weights (±StErr) is higher in female (red, circles) than male (blue, squares) mice (p<0.001).
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pone-0005170-g004: (A) Mean weights of internal organs relative to body weight during T. congolense infection in A/J mice (red), BALB/c mice (blue) and C57BL/6 (green) mice, shown as mean±SD. The mean relative weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold over the course of the infection (p<0.001). There were statistically significant (ANOVA p<0.05) differences in weight between strains at most time points but the largest and perhaps biologically most significant difference was in the spleen where the relative weight in BALB/c mice increased 12 fold and in A/J and C57BL/6 mice it increased about 9.4 fold. (B) The increase in mean spleen and liver weights (±StErr) is higher in female (red, circles) than male (blue, squares) mice (p<0.001).

Mentions: To see whether there was a correlation between anaemia and hepato-splenomegaly, the weights of liver, spleen and kidney were monitored in all three mouse strains during the first 17 days of infection. Weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold respectively over this period, and the change in weight, both absolute and relative to body weight, was highly significant in all cases (ANOVA p<0.001) (Figure 4a). The increase in liver and spleen weights, but not kidney, was significantly (p<0.001) higher in females than in males (Figure 4b). There was a significant difference between strains in spleen weight (ANOVA p< = 0.005) pre-infection and at each sampling day post infection except day 5. BALB/c had the highest weight at all days; this may be associated with particularly high haematopoietic potential in this organ in this strain. There were also significant differences in liver, but not in kidney weight between strains (p<0.05) at most time points. However, the differences in weight were not large and may represent differences in timing of responses as much as fundamental differences in response. Total bodyweight increased slightly over the course of the infection but by less than the total increase in organ weight. This may reflect a loss of muscle mass and be a consequence of the cachexia that is a well-known consequence of the disease.


Mechanisms controlling anaemia in Trypanosoma congolense infected mice.

Noyes HA, Alimohammadian MH, Agaba M, Brass A, Fuchs H, Gailus-Durner V, Hulme H, Iraqi F, Kemp S, Rathkolb B, Wolf E, de Angelis MH, Roshandel D, Naessens J - PLoS ONE (2009)

(A) Mean weights of internal organs relative to body weight during T. congolense infection in A/J mice (red), BALB/c mice (blue) and C57BL/6 (green) mice, shown as mean±SD. The mean relative weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold over the course of the infection (p<0.001). There were statistically significant (ANOVA p<0.05) differences in weight between strains at most time points but the largest and perhaps biologically most significant difference was in the spleen where the relative weight in BALB/c mice increased 12 fold and in A/J and C57BL/6 mice it increased about 9.4 fold. (B) The increase in mean spleen and liver weights (±StErr) is higher in female (red, circles) than male (blue, squares) mice (p<0.001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664899&req=5

pone-0005170-g004: (A) Mean weights of internal organs relative to body weight during T. congolense infection in A/J mice (red), BALB/c mice (blue) and C57BL/6 (green) mice, shown as mean±SD. The mean relative weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold over the course of the infection (p<0.001). There were statistically significant (ANOVA p<0.05) differences in weight between strains at most time points but the largest and perhaps biologically most significant difference was in the spleen where the relative weight in BALB/c mice increased 12 fold and in A/J and C57BL/6 mice it increased about 9.4 fold. (B) The increase in mean spleen and liver weights (±StErr) is higher in female (red, circles) than male (blue, squares) mice (p<0.001).
Mentions: To see whether there was a correlation between anaemia and hepato-splenomegaly, the weights of liver, spleen and kidney were monitored in all three mouse strains during the first 17 days of infection. Weights of liver, spleen and kidney increased 1.9, 10.3 and 1.7 fold respectively over this period, and the change in weight, both absolute and relative to body weight, was highly significant in all cases (ANOVA p<0.001) (Figure 4a). The increase in liver and spleen weights, but not kidney, was significantly (p<0.001) higher in females than in males (Figure 4b). There was a significant difference between strains in spleen weight (ANOVA p< = 0.005) pre-infection and at each sampling day post infection except day 5. BALB/c had the highest weight at all days; this may be associated with particularly high haematopoietic potential in this organ in this strain. There were also significant differences in liver, but not in kidney weight between strains (p<0.05) at most time points. However, the differences in weight were not large and may represent differences in timing of responses as much as fundamental differences in response. Total bodyweight increased slightly over the course of the infection but by less than the total increase in organ weight. This may reflect a loss of muscle mass and be a consequence of the cachexia that is a well-known consequence of the disease.

Bottom Line: Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia.However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng.The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.

ABSTRACT

Background: Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia.

Methodology/principal findings: The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng.

Conclusions/significance: The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection.

Show MeSH
Related in: MedlinePlus