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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.

Author information

1
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
Departments of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada.
4
INSERM, U1016, Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
5
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: scott.gray.owen@utoronto.ca.

Abstract

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

PMID:
28514661
DOI:
10.1016/j.celrep.2017.04.063
[Indexed for MEDLINE]
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