RNAseq study to get insights into opposing susceptibility of the Shiga toxin sensitive ACHN and Stx-refractory Caki-2 cells.

Shiga toxin (Stx) represents the cardinal virulence factor of human-pathogenic enterohaemorrhagic Escherichia coli (EHEC) and is responsible for severe extraintestinal complications such as kidney failure due to damage of renal endothelial cells. The kidney epithelium becomes increasingly recognised in EHEC pathogenesis. Therefore, we investigated human renal epithelial Stx-sensitive ACHN and Stx-refractory Caki-2 cells regarding Stx receptor content and retrograde trafficking to unravel the molecular background of this difference. Though both cell lines exhibited the glycosphingolipid receptor globotriaosylceramide, RNA sequencing revealed a strikingly distinct transcriptomic response to Stx challenge. Employing RNA interference protective effects to ACHN cells were strongest targeting RAB5A and TRAPPC6B, two newly identified host factors related to Stx retrograde cellular trafficking. A cumulative and entire curative effect was obtained when combined with silencing of YKT6. In summary, our transcriptomic approach revealed novel subcellular targets, which might help to develop new therapeutic measures to protect from Stx-mediated kidney failure.