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 intracellularbacterial proliferation. Strikingly, IECs lackingTIFA 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.
Highlights
Innate recognition of pathogen-associated molecular patterns (PAMPs), invariant molecules broadly present in microbes yet different from self, alert the host to a microbial presence and, depending on the context in which they are recognized, elicit an immune response that is commensurate with the microbial threat presented
Considering the abundance of literature on NOD1-dependent detection of Shigella, we began by definitively assessing whether NOD1 and NOD2 could account for the entirety of the IL-8 response to invasive Shigella
TRAF-interacting forkhead-associated protein A (TIFA) KO cells were not compromised in their response to the NOD1 agonist C12-iE-DAP or the cytokine tumor necrosis factor alpha (TNF-a) (Figure 1B)
Summary
Innate recognition of pathogen-associated molecular patterns (PAMPs), invariant molecules broadly present in microbes yet different from self, alert the host to a microbial presence and, depending on the context in which they are recognized, elicit an immune response that is commensurate with the microbial threat presented. Intestinal epithelial cells (IECs), through mechanisms that remain poorly defined, maintain immune homeostasis with trillions of commensal microbiota, yet mount robust inflammatory responses to pathogenic infections (Peterson and Artis, 2014). In this respect, IECs act as frontline sentinels for invasive pathogens. A classic model for invasive intestinal pathogens is Shigella flexneri (Shigella), a foodborne bacterium that invades the colonic epithelium and causes shigellosis in humans. The lingering Shigella-induced cytokine responses in mice deficient for RIP2 (Sorbara et al, 2013; Travassos et al, 2010), the adaptor essential for both NOD1 and NOD2 signaling, hints at the existence of additional NF-kB-activating sensors for invasive Shigella
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
