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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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Haemoglobin titres in C57BL/6 (green), A/J (red) and BALB/c mice (blue) after infection with T. congolense, and uninfected C57BL/6 mice (grey, broken line), shown as mean±SD.Each point is an average of ten mice. Haemoglobin declines rapidly in all mouse strains until the first peak of parasitaemia after which it recovers to almost baseline levels in BALB/c mice, partially recovers in A/J mice but continues to decline in C57BL/6 mice.
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pone-0005170-g002: Haemoglobin titres in C57BL/6 (green), A/J (red) and BALB/c mice (blue) after infection with T. congolense, and uninfected C57BL/6 mice (grey, broken line), shown as mean±SD.Each point is an average of ten mice. Haemoglobin declines rapidly in all mouse strains until the first peak of parasitaemia after which it recovers to almost baseline levels in BALB/c mice, partially recovers in A/J mice but continues to decline in C57BL/6 mice.

Mentions: Three additional T. congolense infection experiments were carried out in order to compare anaemia development between susceptible A/J, tolerant C57BL/6 and intermediately susceptible BALB/c mice. Mean haemoglobin titres were measured in ten mice of each strain up to day 30 post infection (pi). After infection, a decrease in haemoglobin titres was almost immediately noticeable in all three mouse strains (Fig. 2). This initial anaemia reached a nadir by day 10 pi in A/J mice and haemoglobin titres partially recovered thereafter. C57BL/6 mice never recovered and developed severe anaemia. The haemoglobin titre in BALB/c mice recovered even faster than the titre in A/J mice. Comparison of the mean haemoglobin titres in the three mouse strains on day 17 pi in three different infection experiments (Table 1) confirmed that C57BL/6 mice are the most susceptible to anaemia development, while BALB/c mice are the most resistant. In a previous evaluation of anaemia in A/J and C57BL/6 over a shorter time period (18 days) we also found that A/J had higher haemoglobin titres than C57BL/6 [29]. However, in that case A/J had higher titres from the start and the differences remained constant over the 18 days of the experiment. The difference in timing and size of the relative haemoglobin levels between strains between experiments may be due to the high variability in haemoglobin levels (note the large error bars in figure 2) but in both cases C57BL/6 developed a more severe anaemia than A/J.


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)

Haemoglobin titres in C57BL/6 (green), A/J (red) and BALB/c mice (blue) after infection with T. congolense, and uninfected C57BL/6 mice (grey, broken line), shown as mean±SD.Each point is an average of ten mice. Haemoglobin declines rapidly in all mouse strains until the first peak of parasitaemia after which it recovers to almost baseline levels in BALB/c mice, partially recovers in A/J mice but continues to decline in C57BL/6 mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0005170-g002: Haemoglobin titres in C57BL/6 (green), A/J (red) and BALB/c mice (blue) after infection with T. congolense, and uninfected C57BL/6 mice (grey, broken line), shown as mean±SD.Each point is an average of ten mice. Haemoglobin declines rapidly in all mouse strains until the first peak of parasitaemia after which it recovers to almost baseline levels in BALB/c mice, partially recovers in A/J mice but continues to decline in C57BL/6 mice.
Mentions: Three additional T. congolense infection experiments were carried out in order to compare anaemia development between susceptible A/J, tolerant C57BL/6 and intermediately susceptible BALB/c mice. Mean haemoglobin titres were measured in ten mice of each strain up to day 30 post infection (pi). After infection, a decrease in haemoglobin titres was almost immediately noticeable in all three mouse strains (Fig. 2). This initial anaemia reached a nadir by day 10 pi in A/J mice and haemoglobin titres partially recovered thereafter. C57BL/6 mice never recovered and developed severe anaemia. The haemoglobin titre in BALB/c mice recovered even faster than the titre in A/J mice. Comparison of the mean haemoglobin titres in the three mouse strains on day 17 pi in three different infection experiments (Table 1) confirmed that C57BL/6 mice are the most susceptible to anaemia development, while BALB/c mice are the most resistant. In a previous evaluation of anaemia in A/J and C57BL/6 over a shorter time period (18 days) we also found that A/J had higher haemoglobin titres than C57BL/6 [29]. However, in that case A/J had higher titres from the start and the differences remained constant over the 18 days of the experiment. The difference in timing and size of the relative haemoglobin levels between strains between experiments may be due to the high variability in haemoglobin levels (note the large error bars in figure 2) but in both cases C57BL/6 developed a more severe anaemia than A/J.

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