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Τρίτη 16 Μαΐου 2017

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

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Ryan G. Gaudet, Cynthia X. Guo, Raphael Molinaro, Haila Kottwitz, John R. Rohde, Anne-Sophie Dangeard, Cécile Arrieumerlou, Stephen E. Girardin, Scott D. Gray-Owen
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.

Graphical abstract

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Teaser

Gaudet et al. describe an innate immune pathway that confers the ability to detect replicating bacteria free in the host cytosol. This pathway, mediated by the protein TIFA, informs the host to the magnitude of intracellular bacterial proliferation, providing the contextual signal to dramatically amplify the inflammatory response to virulent pathogens.


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