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The Protozoan Parasite Theileria Annulata Alters the Differentiation

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The Protozoan Parasite Theileria Annulata Alters the Differentiation International Journal for Parasitology 39 (2009) 1099–1108 Contents lists available at ScienceDirect International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors Kirsty Jensen *, Giles D. Makins, Anna Kaliszewska, Martin J. Hulme, Edith Paxton, Elizabeth J. Glass Division of Genetics & Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin Biocentre, Midlothian, EH25 9PS, UK article info abstract Article history: The tick-borne protozoan parasite Theileria annulata causes a debilitating disease of cattle called Tropical Received 7 January 2009 Theileriosis. The parasite predominantly invades bovine macrophages (m/) and induces host cell Received in revised form 13 February 2009 transformation by a mechanism that has not been fully elucidated. Infection is associated with loss of Accepted 16 February 2009 characteristic m/ 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/ differentiation marker c-maf. The up-regulation of c-maf mRNA levels observed during bovine monocyte differentiation to Keywords: m/ was suppressed by T. annulata infection. Furthermore, mRNA levels for c-maf and the closely related Theileria annulata transcription factor mafB were significantly lower in established T. annulata-infected cell-lines than in Bovine Host-pathogen interactions bovine monocyte-derived m/. Treatment of T. annulata-infected cells with the theileriacidal drug MAF transcription factors buparvaquone induced up-regulation of c-maf and mafB, which correlated with altered expression of Macrophage differentiation 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/ differentiation. We believe these results provide the first direct evidence that T. annulata modulates the host m/ 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/. Ó 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. 1. Introduction of infection (Campbell et al., 1995). In addition, infected cells dis- seminate through lymphoid tissue and non-lymphoid organs The tick-borne apicomplexan parasite Theileria annulata is the including the heart, lungs and brain, causing haemorrhagic lesions causative agent of the cattle disease Tropical Theileriosis, which (Forsyth et al., 1999). The mechanism behind the transformation is of major economic importance in countries in Northern Africa event has been extensively studied, but is not fully understood (re- and Asia. The infectious sporozoite stage of the parasite exhibits viewed Dobbelaere and Kuenzi, 2004; Heussler et al., 2006; Plattner cell tropism, predominantly invading bovine macrophages (m/) and Soldati-Favre, 2008). This work has revealed an extremely com- and to a lesser extent B lymphocytes (Glass et al., 1989). Within plex network of interactions between the parasite and host cell, these cells the parasite differentiates into the multinucleated involving many cellular pathways, including; NF-jB(Heussler schizont stage, which is associated with much of the disease et al., 2002), c-myc (Dessauge et al., 2005), SRC-related tyrosine pathology. kinase (Eichhorn and Dobbelaere, 1994), c-jun NH2-terminal kinase A unique feature of T. annulata, and the closely related parasite (JNK) (Galley et al., 1997; Chaussepied et al., 1998), phosphoinosi- Theileria parva, is the ability of the schizont stage to induce host cell tide-3 kinase (Baumgartner et al., 2000), protein kinase A (Guergnon transformation without involving the integration of parasite DNA et al., 2006) and Notch (Chaussepied et al., 2006). into the host genome. This leads to continuous proliferation of the Theileria annulata infection alters the phenotype and function of infected cell and parasite (Spooner et al., 1989). These cells disrupt the host m/ (reviewed by Glass and Jensen, 2007). Phenotypic the morphology and function of the lymph node draining the site changes include the down-regulation of m/ markers CD14 and CD11b, together with increased surface expression of CD2 and * Corresponding author. Tel.: +44 131 5274200; fax: +44 131 4400434. bovine major histocompatibility complex (BoLA) class II genes E-mail address: [email protected] (K. Jensen). (Glass and Spooner, 1990; Brown et al., 1995; Sager et al., 1997; 0020-7519/$36.00 Ó 2009 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijpara.2009.02.020 1100 K. Jensen et al. / International Journal for Parasitology 39 (2009) 1099–1108 Glass and Jensen, 2007). Several m/ functions are impaired by kept on pasture. All experimental protocols were authorized under T. annulata, including phagocytosis and the production of nitric the UK Animals (Scientific Procedures) Act, 1986. oxide, superoxide and pro-inflammatory cytokines in response to stimulation by phorbol 12-myristate 13-acetate and lipopolysac- 2.2. Isolation of bovine monocytes charide (LPS) (Sager et al., 1997). Transformation of the infected m/ is reversible and requires the presence of live parasites (Sager Peripheral blood was collected aseptically into acid citrate dex- et al., 1997). Treatment of infected cells with the theileriacidal drug trose (ACD) and immediately stored on ice. Peripheral blood mono- buparvaquone results in a decrease in cell-cycling, increased sur- nuclear cells (PBMC) were separated under cold conditions by face expression of CD14 and CD11b, and the reacquisition of density gradient centrifugation as described previously (Jensen phagocytosis function (Sager et al., 1997). et al., 2006). Peripheral monocytes were isolated from PBMC by M/ are an end product of the differentiation of myeloid progen- positive selection using the monoclonal antibody IL-A24, which itor cells via blood monocytes. Monocytes have the potential to dif- recognizes signal-regulatory protein alpha (SIRPA) (Brooke et al., ferentiate into different subsets of m/ and dendritic cells (DC), 1998), and the MACS system (Miltenyi Biotec) as described previ- which play a multitude of important roles in the immune response ously (Jensen et al., 2006). Fluorescence-activated cell sorting (Iwasaki and Akashi, 2007; Geissmann et al., 2008; Serbina et al., (FACS) analysis confirmed that the cell purity exceeded 95% (data 2008). It has been postulated, from the phenotypic and functional not shown). changes associated with T. annulata infection, that the parasite induces the m/ to revert back to a de-differentiated state, which 2.3. Infection and stimulation of bovine monocytes may be a strategy utilized by the parasite to subvert the m/ defence response (Sager et al., 1997). However, T. annulata-infected Resting peripheral monocytes from five cattle were resus- cells exhibit up-regulation of BoLA class II molecules and pro- pended at 4 x 106 cells/ml in RPMI-1640 medium supplemented inflammatory cytokines (Brown et al., 1995; McGuire et al., with 20% FBS and aliquoted into a 12-well plate. One half of 2004), enhanced antigen-presenting capabilities (Glass and Spoo- each sample were infected with T. annulata (Ankara) sporozoites ner, 1990) and induce neighbouring T lymphocytes, including in homogenized infected tick (Hyalomma anatolicum) prepara- naïve T cells, to activate and proliferate (Campbell et al., 1995). tions (kindly provided by Dr. Patricia Preston, University of Edin- Therefore the infected m/ does not resemble monocytes or mye- burgh, UK), as described previously (Jensen et al., 2008). Briefly, loid progenitor cells. an equal volume of sporozoite suspension at 0.25 tick equiva- The differentiation of m/ from myeloid progenitor cells is a lents/ml in RPMI-1640 medium supplemented with 40% FBS tightly controlled process regulated by transcription factor activity was added to the monocytes and incubated at 37 °Cina5% (reviewed by Hume and Himes, 2003; Friedman, 2007). Transcrip- CO2 incubator. The sporozoite concentration had been previously tion factors involved include the Ets family member spleen focus optimized to maximize the percentage of monocytes being in- forming virus (SFFV) proviral integration oncogene spi1 (Pu.1), fected (data not shown). As a medium-only negative control, the core binding family member runt-related transcription factor an equal volume of RPMI-1640 medium supplemented with 1 (RUNX1) and two members of the musculoaponeurotic fibrosar- 40% FBS was added to the other half of each monocyte sample. coma oncogene (MAF) transcription factor family, c-MAF and Cells were harvested at 0 and 72 h p.i. The infected monocytes MAFB. Expression of human c-MAF increases progressively from were pelleted, washed with PBS and RNA was immediately iso- myeloid progenitor cells to m/ and is, therefore,
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