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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 expression of musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors c-MAF and MAFB 72 h post-activation and Theileria annulata infection. Quantitative reverse transcription-PCR analysis of (A) c-MAF and (B) MAFB average log2 mRNA fold change after 72 h in culture compared with resting monocytes. M denotes medium only, Ta denotes T. annulata-infected tick preparations and U denotes uninfected tick preparations. The error bars indicate the standard error for monocytes isolated from four cattle. The statistical significance of the difference in fold change is indicated and ** denotes P ⩽ 0.001.
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fig2: The expression of musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors c-MAF and MAFB 72 h post-activation and Theileria annulata infection. Quantitative reverse transcription-PCR analysis of (A) c-MAF and (B) MAFB average log2 mRNA fold change after 72 h in culture compared with resting monocytes. M denotes medium only, Ta denotes T. annulata-infected tick preparations and U denotes uninfected tick preparations. The error bars indicate the standard error for monocytes isolated from four cattle. The statistical significance of the difference in fold change is indicated and ** denotes P ⩽ 0.001.

Mentions: The schizont stage of T. annulata, which is the stage associated with host cell proliferation, develops within 2 days after sporozoite infection of the mϕ (Jura et al., 1983). To investigate whether the regulation of mϕ differentiation is required for host cell transformation, c-MAF mRNA levels were measured in monocytes cultured in the presence or absence of T. annulata sporozoites for 3 days, before parasite-induced host cell proliferation becomes apparent. The bovine monocytes were cultured for 3 days in tissue culture plates, which induces an intermediate differentiation state in human monocytes (Martinez et al., 2006; Lehtonen et al., 2007). The expression of c-MAF was observed to increase by on average 481-fold after this period (Fig. 2A, M), which was significantly greater than observed after 7 days culture in Teflon bags (Fig. 1). This discrepancy may be due to the different culture conditions or may result from c-MAF levels decreasing in the latter stages of 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 expression of musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors c-MAF and MAFB 72 h post-activation and Theileria annulata infection. Quantitative reverse transcription-PCR analysis of (A) c-MAF and (B) MAFB average log2 mRNA fold change after 72 h in culture compared with resting monocytes. M denotes medium only, Ta denotes T. annulata-infected tick preparations and U denotes uninfected tick preparations. The error bars indicate the standard error for monocytes isolated from four cattle. The statistical significance of the difference in fold change is indicated and ** denotes P ⩽ 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: The expression of musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors c-MAF and MAFB 72 h post-activation and Theileria annulata infection. Quantitative reverse transcription-PCR analysis of (A) c-MAF and (B) MAFB average log2 mRNA fold change after 72 h in culture compared with resting monocytes. M denotes medium only, Ta denotes T. annulata-infected tick preparations and U denotes uninfected tick preparations. The error bars indicate the standard error for monocytes isolated from four cattle. The statistical significance of the difference in fold change is indicated and ** denotes P ⩽ 0.001.
Mentions: The schizont stage of T. annulata, which is the stage associated with host cell proliferation, develops within 2 days after sporozoite infection of the mϕ (Jura et al., 1983). To investigate whether the regulation of mϕ differentiation is required for host cell transformation, c-MAF mRNA levels were measured in monocytes cultured in the presence or absence of T. annulata sporozoites for 3 days, before parasite-induced host cell proliferation becomes apparent. The bovine monocytes were cultured for 3 days in tissue culture plates, which induces an intermediate differentiation state in human monocytes (Martinez et al., 2006; Lehtonen et al., 2007). The expression of c-MAF was observed to increase by on average 481-fold after this period (Fig. 2A, M), which was significantly greater than observed after 7 days culture in Teflon bags (Fig. 1). This discrepancy may be due to the different culture conditions or may result from c-MAF levels decreasing in the latter stages of 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