title: Transferrin receptor induction in Toxoplasma gondii-infected HFF is associated with increased iron-responsive protein 1 activity and is mediated by secreted factors.
abstract: Infection with the apicomplexan parasite Toxoplasma gondii results in a significant alteration of the host-cell transcriptional profile. We have previously shown that the transferrin receptor (TfR) is specifically up-regulated in T. gondii-infected human fibroblasts but not in host cells infected with the bacterial pathogens Salmonella Typhimurium and Chlamydia trachomatis. In this report, we describe the prerequisites and physiological conditions that are associated with this pathogen-specific gene induction. Band-shift assays revealed that T. gondii infection resulted in increased activity in the iron response protein IRP1, which, in this state, stabilizes TfR mRNA from degradation. Although T. gondii depends on host-cell iron as demonstrated by sensitivity to deferoxamine, a parasite-induced iron starvation is not responsible for TfR up-regulation. The increased iron availability due to treatment with holotransferrin and FeNTA did not prevent TfR induction nor was the transferrin-independent iron-transporter NRAMP2 up-regulated in infected host cells. In addition, inhibition of parasite replication by drug treatment did not prevent TfR up-regulation. Instead, TfR induction was sensitive to cycloheximide and could be induced by treatment with conditioned media from infected human fibroblasts. Together our findings suggest that the T. gondii-specific TfR up-regulation is not due to a direct interaction of parasitic factors with the iron-uptake machinery of the host cell but is instead mediated indirectly as a result of secreted host cell- or parasite-derived factors.
authors.affiliation: Institute for Medical Microbiology, University of Göttingen, 37075, Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gail
authors.forename: Uwe
authors.initials: U
authors.lastname: Gross
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bohne
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D007501:Iron / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000096:biosynthesis* / Q000235:genetics*; D014122:Toxoplasma / Q000472:pathogenicity*; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D035925:Iron-Regulatory Proteins; D011990:Receptors, Transferrin; D007501:Iron