Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells

Nat Commun. 2021 Jun 7;12(1):3392. doi: 10.1038/s41467-021-23593-z.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bystander Effect / genetics*
  • Bystander Effect / immunology
  • Disease Models, Animal
  • Down-Regulation / immunology
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Endoplasmic Reticulum Stress / immunology
  • Endoribonucleases / metabolism
  • HMGB1 Protein / metabolism
  • HeLa Cells
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Listeria monocytogenes / immunology
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology
  • MicroRNAs / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA-Seq
  • Salmonella Infections / genetics
  • Salmonella Infections / immunology*
  • Salmonella Infections / microbiology
  • Salmonella typhimurium / immunology*
  • Salmonella typhimurium / pathogenicity
  • Shigella flexneri / immunology
  • Swine


  • E2F1 Transcription Factor
  • E2F1 protein, human
  • HMGB1 Protein
  • HMGB1 protein, human
  • MicroRNAs
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases