Innate Recognition of Intracellular Bacterial Growth Is Driven by the TIFA-Dependent Cytosolic Surveillance Pathway

Cell Rep. 2017 May 16;19(7):1418-1430. doi: 10.1016/j.celrep.2017.04.063.


Intestinal epithelial cells (IECs) act as sentinels for incoming pathogens. Cytosol-invasive bacteria, such as Shigella flexneri, trigger a robust pro-inflammatory nuclear factor κB (NF-κB) response from IECs that is believed to depend entirely on the peptidoglycan sensor NOD1. We found that, during Shigella infection, the TRAF-interacting forkhead-associated protein A (TIFA)-dependent cytosolic surveillance pathway, which senses the bacterial metabolite heptose-1,7-bisphosphate (HBP), functions after NOD1 to detect bacteria replicating free in the host cytosol. Whereas NOD1 mediated a transient burst of NF-κB activation during bacterial entry, TIFA sensed HBP released during bacterial replication, assembling into large signaling complexes to drive a dynamic inflammatory response that reflected the rate of intracellular bacterial proliferation. Strikingly, IECs lacking TIFA were unable to discriminate between proliferating and stagnant intracellular bacteria, despite the NOD1/2 pathways being intact. Our results define TIFA as a rheostat for intracellular bacterial replication, escalating the immune response to invasive Gram-negative bacteria that exploit the host cytosol for growth.

Keywords: NOD-like receptors; PAMP; Shigella; TIFA; heptose; inflammation; innate immunity; intracellular bacteria; pattern recognition.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cytosol / metabolism*
  • HeLa Cells
  • Humans
  • Immunity, Innate*
  • Intracellular Space / microbiology*
  • Nod1 Signaling Adaptor Protein / metabolism
  • Phosphates / metabolism
  • Shigella flexneri / growth & development*
  • Signal Transduction*
  • Vacuoles / metabolism


  • Adaptor Proteins, Signal Transducing
  • Nod1 Signaling Adaptor Protein
  • Phosphates
  • TIFA protein, human