Enteroaggregative E. coli Adherence to Human Heparan Sulfate Proteoglycans Drives Segment and Host Specific Responses to Infection

Abstract

Enteroaggregative Escherichia coli (EAEC) is a significant cause of acute and chronic diarrhea, foodborne outbreaks, infections of the immunocompromised, and growth stunting in children in developing nations. There is no vaccine and resistance to antibiotics is rising. Unlike related E. coli pathotypes that are often associated with acute bouts of infection, EAEC is associated with persistent diarrhea and subclinical long-term colonization. Several secreted virulence factors have been associated with EAEC pathogenesis and linked to disease in humans, less certain are the molecular drivers of adherence to the intestinal mucosa. We previously established human intestinal enteroids (HIEs) as a model system to study host-EAEC interactions and aggregative adherence fimbriae A (AafA) as a major driver of EAEC adherence to HIEs. Here, we report a large-scale assessment of the host response to EAEC adherence from all four segments of the intestine across at least three donor lines for five E. coli pathotypes. The data demonstrate that the host response in the duodenum is driven largely by the infecting pathotype, whereas the response in the colon diverges in a patient-specific manner. Major pathways altered in gene expression in each of the four enteroid segments differed dramatically, with responses observed for inflammation, apoptosis and an overwhelming response to different mucin genes. In particular, EAEC both associated with large mucus droplets and specific mucins at the epithelial surface, binding

Salmonella enterica Serovar Typhimurium Exploits Cycling through Epithelial Cells To Colonize Human and Murine Enteroids

“…It should be noted that several additional mechanisms for luminal population restriction (e.g., commensal microbiota competition, soluble IgA coating, and trapping in mucus) are at play in the more complex intact gut (71). Moreover, our results pertain specifically to human and murine jejunal enteroids, but intestinal-segment-specific differences may well exist, as has been noted for other pathogens (61)(62)(63).…”

A versatile human intestinal organoid-derived epithelial monolayer model for the study of enteric pathogens

“…Robust infection of the appropriate site of GI tract was observed with each pathovar, with comparable rates of adherence and minimal recoveries upon gentamicin to indicate a lack of invasion. The infection patterns and microscopic evaluations are in agreement with previous and recent analyses of organoid monolayer-based systems (11, 56, 57, 72), as well as with established literature regarding actin association and pedestal formation, or aggregative adherence patterns (37, 38). As with Shigella and Salmonella analyses, the future applications of the HIODEM model system with all E. coli pathotypes are broad and expected to provide key insights into human-specific pathology, including infection analyses in other segments of the GI tract for each pathovar.…”

Targeting of Mammalian Glycans Enhances Phage Predation in the Gastrointestinal Tract

“…Several pathogens, including bacteria and human-pathogenic viruses, have been shown to bind to HS and use them as receptors (83)(84)(85). Rather remarkably, around the same time as this discovery, our lab has discovered that EAEC also uses HSPGs as the receptor (86). It is tempting to speculate that this property might have been also acquired by phage, as suggested here.…”