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The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors.

Jensen K, Makins GD, Kaliszewska A, Hulme MJ, Paxton E, Glass EJ - Int. J. Parasitol. (2009)

Bottom Line: Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi.We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation.Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics & Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin Biocentre, Midlothian EH25 9PS, UK. Kirsty.Jensen@roslin.ed.ac.uk

ABSTRACT
The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades bovine macrophages (m phi) and induces host cell transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of characteristic m phi functions and phenotypic markers, indicative of host cell de-differentiation. We have investigated the effect of T. annulata infection on the expression of the m phi differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to m phi was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi. Treatment of T. annulata-infected cells with the theileriacidal drug buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of down-stream target genes, e.g. up-regulation of integrin B7 and down-regulation of IL12A. Furthermore, T. annulata infection is associated with the suppression of the transcription factors, Pu.1 and RUNX1, and colony stimulating factor 1 receptor (CSF1R) which are also involved in the regulation of monocyte/m phi differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation. Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.

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The musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factor c-MAF is a marker of macrophage (mϕ) differentiation. Shown are average log2 mRNA fold difference in bovine monocytes and bovine monocyte-derived mϕ compared with a standard resting monocyte sample for c-MAF (grey bars) and closely related transcription factor MAFB (white bars) The error bars indicate the standard error for eight biological replicates. The statistical significance of the difference in mRNA levels between the cell types is indicated and ** denotes P ⩽ 0.001.
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fig1: The musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factor c-MAF is a marker of macrophage (mϕ) differentiation. Shown are average log2 mRNA fold difference in bovine monocytes and bovine monocyte-derived mϕ compared with a standard resting monocyte sample for c-MAF (grey bars) and closely related transcription factor MAFB (white bars) The error bars indicate the standard error for eight biological replicates. The statistical significance of the difference in mRNA levels between the cell types is indicated and ** denotes P ⩽ 0.001.

Mentions: The expression of c-MAF has previously been shown to be a marker of human mϕ differentiation (Martinez et al., 2006; Liu et al., 2008). To investigate whether this was also true of bovine mϕ, the expression of c-MAF and MAFB was measured in bovine mϕ and compared with that found in freshly isolated, resting monocytes. Bovine mϕ were generated from peripheral monocytes by culturing for 7 days in Teflon bags as described previously (Jungi et al., 1996) and exhibited typical mϕ phenotypic characteristics, e.g. morphology and cell marker expression (data not shown). The expression of c-MAF and MAFB was measured by qRT-PCR and found to be consistent between bovine monocyte samples (Fig. 1). The level of c-MAF expression was up-regulated in bovine mϕ, by on average 43-fold, compared with freshly isolated monocytes (P < 0.001). MAFB expression in bovine mϕ did not differ significantly from that observed in resting monocytes. This result confirms that c-MAF, but not MAFB, is a marker of bovine monocyte to mϕ differentiation.


The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors.

Jensen K, Makins GD, Kaliszewska A, Hulme MJ, Paxton E, Glass EJ - Int. J. Parasitol. (2009)

The musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factor c-MAF is a marker of macrophage (mϕ) differentiation. Shown are average log2 mRNA fold difference in bovine monocytes and bovine monocyte-derived mϕ compared with a standard resting monocyte sample for c-MAF (grey bars) and closely related transcription factor MAFB (white bars) The error bars indicate the standard error for eight biological replicates. The statistical significance of the difference in mRNA levels between the cell types is indicated and ** denotes P ⩽ 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2723921&req=5

fig1: The musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factor c-MAF is a marker of macrophage (mϕ) differentiation. Shown are average log2 mRNA fold difference in bovine monocytes and bovine monocyte-derived mϕ compared with a standard resting monocyte sample for c-MAF (grey bars) and closely related transcription factor MAFB (white bars) The error bars indicate the standard error for eight biological replicates. The statistical significance of the difference in mRNA levels between the cell types is indicated and ** denotes P ⩽ 0.001.
Mentions: The expression of c-MAF has previously been shown to be a marker of human mϕ differentiation (Martinez et al., 2006; Liu et al., 2008). To investigate whether this was also true of bovine mϕ, the expression of c-MAF and MAFB was measured in bovine mϕ and compared with that found in freshly isolated, resting monocytes. Bovine mϕ were generated from peripheral monocytes by culturing for 7 days in Teflon bags as described previously (Jungi et al., 1996) and exhibited typical mϕ phenotypic characteristics, e.g. morphology and cell marker expression (data not shown). The expression of c-MAF and MAFB was measured by qRT-PCR and found to be consistent between bovine monocyte samples (Fig. 1). The level of c-MAF expression was up-regulated in bovine mϕ, by on average 43-fold, compared with freshly isolated monocytes (P < 0.001). MAFB expression in bovine mϕ did not differ significantly from that observed in resting monocytes. This result confirms that c-MAF, but not MAFB, is a marker of bovine monocyte to mϕ differentiation.

Bottom Line: Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi.We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation.Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics & Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin Biocentre, Midlothian EH25 9PS, UK. Kirsty.Jensen@roslin.ed.ac.uk

ABSTRACT
The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Theileriosis. The parasite predominantly invades bovine macrophages (m phi) and induces host cell transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of characteristic m phi functions and phenotypic markers, indicative of host cell de-differentiation. We have investigated the effect of T. annulata infection on the expression of the m phi differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to m phi was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in bovine monocyte-derived m phi. Treatment of T. annulata-infected cells with the theileriacidal drug buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of down-stream target genes, e.g. up-regulation of integrin B7 and down-regulation of IL12A. Furthermore, T. annulata infection is associated with the suppression of the transcription factors, Pu.1 and RUNX1, and colony stimulating factor 1 receptor (CSF1R) which are also involved in the regulation of monocyte/m phi differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host m phi differentiation state, which may diminish the defence capabilities of the infected cell and/or promote cell proliferation. Musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors play an important role in cell proliferation, differentiation and survival; therefore, regulation of these genes may be a major mechanism employed by T. annulata to survive within the infected m phi.

Show MeSH
Related in: MedlinePlus