Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

Abstract

EnteropathogenicEscherichia coli(EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.

Salmonella Typhimurium Co-Opts the Host Type I IFN System To Restrict Macrophage Innate Immune Transcriptional Responses Selectively

“…While we show clearly that the production of IFN-β in vivo rapidly accelerates the spread of S T infection to secondary sites (Figure 1B), this is clearly not the case for all pathogenic bacteria (19, 38) nor even all Gram negative bacteria. Indeed, Y. entercolitica , which shares a common oral route of infection with S T, is suppressed by TRIF-dependent IFN production (57).…”

The Roles of Type I Interferon in Bacterial Infection

“…The arrangement and density of these proteins determines the permeability of the epithelial barrier and act to confine local tissue infections (LeMessurier et al, 2013; Long et al, 2014). Type I IFNs, augmented by RNase-L, an ISG that mediates induction of type I IFNS, promote the expression of tight junction proteins (LeMessurier et al, 2013).…”

A systematic review of gut‐immune‐brain mechanisms in Autism Spectrum Disorder

“…The “leaky gut theory” postulates that an exceptionally increased permeability of the intestinal mucosa barrier represents a fundamental mechanism underlying autistic pathology (de Magistris et al, ; D'Eufemia et al, ; Horvath & Perman, ; Panksepp, ; Wakefield et al, ). Studies on subgroups of ASD subjects have revealed that this deficiency is partly contributed by (a) alterations in microbial composition, with an overrepresentation of bacterium Akkermansia muciniphila , known to degrade the mucus lining (Wang et al, ), (b) prevalence of Clostridia and reduced abundance of Bifidobacteria , increasing pro‐inflammatory cytokines production, which aggravates mucosa permeability (Heberling, Dhurjati, & Sasser, ), (c) elevated plasma levels of zonulin, a protein that regulates permeability (Esnafoglu et al, ), (d) decreased amounts of tight junction proteins at the intestinal barrier (Fiorentino et al, ), potentially due to increased toxins from Clostridia (Hecht, Pothoulakis, LaMont, & Madara, ), (e) infection by Escherichia coli , which leads to transformation of actin and tight junction structures (Long, Nisa, Donnenberg, & Hassel, ), (f) abundance of Candida fungi, which expresses root‐like formations that invade the intestinal wall (de Magistris et al, ), and (g) increased levels of claudin, a molecule that contributes to pores formation (Fiorentino et al, ). Individuals with both autistic and gastrointestinal disorders exhibit a distinct cytokine (Ashwood & Wakefield, ; Torrente et al, ) and regulatory (Ashwood, Anthony, Torrente, & Wakefield, ) profile.…”