title: The protozoan parasite Theileria annulata alters the differentiation state of the infected macrophage and suppresses musculoaponeurotic fibrosarcoma oncogene (MAF) transcription factors.
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.
authors.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
authors.forename: Kirsty
authors.initials: K
authors.lastname: Jensen
authors.forename: Giles D
authors.initials: GD
authors.lastname: Makins
authors.forename: Anna
authors.initials: A
authors.lastname: Kaliszewska
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hulme
authors.forename: Edith
authors.initials: E
authors.lastname: Paxton
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Glass
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000469:parasitology; D054337:Cell Dedifferentiation; D002454:Cell Differentiation / Q000235:genetics*; D006790:Host-Parasite Interactions; D008264:Macrophages / Q000166:cytology / Q000469:parasitology* / Q000502:physiology; D050977:Maf Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009285:Naphthoquinones / Q000627:therapeutic use; D010641:Phenotype; D016796:Theileria annulata / Q000235:genetics; D013801:Theileriasis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000981:Antiprotozoal Agents; D050977:Maf Transcription Factors; D009285:Naphthoquinones; C046326:buparvaquone