Abstract
Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.
Highlights
Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection
To investigate the importance of E2F1 downregulation to the miRNA expression changes occurring during Salmonella infection, we have performed a comparative analysis of miRNA expression datasets obtained from small RNA sequencing of Salmonella-infected HeLa cells and E2F1 knockdown cells
The comparison of the miRNA expression profiles revealed a clear trend for miRNAs decreased in E2F1 knockdown cells to be decreased in Salmonella-infected cells (Fig. 1b), with 144 (26% of total; 56% of Salmonella downregulated) miRNAs downregulated in both conditions
Summary
Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. We have shown that Shigella flexneri infection induces plasma membrane remodeling in infected and bystander cells, through the activation of the acid sphingomyelinase and strong accumulation of ceramide at the cell surface[13] These changes of membrane composition determine a depletion of permissive bacterial binding sites, constituting a cell-autonomous defense mechanism that protects cells from infection by non-motile bacteria. Given the constant evolutionary pressure of host and pathogen to obtain a competitive advantage, it is conceivable that both have evolved alternative strategies to exploit bystander cell functions
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