Cytokine-dependent and–independent gene expression changes and cell cycle block revealed in <it<Trypanosoma cruzi</it<-infected host cells by comparative mRNA profiling

<p<Abstract</p< <p<Background</p< <p<The requirements for growth and survival of the intracellular pathogen <it<Trypanosoma cruzi </it<within mammalian host cells are poorly understood. Transcriptional profiling of the host cell response to infection serves...
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<p<Abstract</p< <p<Background</p< <p<The requirements for growth and survival of the intracellular pathogen <it<Trypanosoma cruzi </it<within mammalian host cells are poorly understood. Transcriptional profiling of the host cell response to infection serves as a rapid read-out for perturbation of host physiology that, in part, reflects adaptation to the infective process. Using Affymetrix oligonucleotide array analysis we identified common and disparate host cell responses triggered by <it<T. cruzi </it<infection of phenotypically diverse human cell types.</p< <p<Results</p< <p<We report significant changes in transcript abundance in <it<T. cruzi</it<-infected fibroblasts, endothelial cells and smooth muscle cells (2852, 2155 and 531 genes respectively; fold-change ≥ 2, p-value < 0.01) 24 hours post-invasion. A prominent type I interferon response was observed in each cell type, reflecting a secondary response to secreted cytokine in infected cultures. To identify a core cytokine-independent response in <it<T. cruzi</it<-infected fibroblasts and endothelial cells transwell plates were used to distinguish cytokine-dependent and -independent gene expression profiles. This approach revealed the induction of metabolic and signaling pathways involved in cell proliferation, amino acid catabolism and response to wounding as common themes in <it<T. cruzi</it<-infected cells. In addition, the downregulation of genes involved in mitotic cell cycle and cell division predicted that <it<T. cruzi </it<infection may impede host cell cycle progression. The observation of impaired cytokinesis in <it<T. cruzi</it<-infected cells, following nuclear replication, confirmed this prediction.</p< <p<Conclusion</p< <p<Metabolic pathways and cellular processes were identified as significantly altered at the transcriptional level in response to <it<T. cruzi </it<infection in a cytokine-independent manner. Several of these alterations are supported by previous studies of <it<T. cruzi </it<metabolic requirements or effects on the host. However, our methods also revealed a <it<T. cruzi</it<-dependent block in the host cell cycle, at the level of cytokinesis, previously unrecognized for this pathogen-host cell interaction.</p< Ausführliche Beschreibung