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

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

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Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
INSERM, U1016, Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:


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.


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

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