Abstract
Enteropathogenic E. coli (EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC or escN mutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues. Metabolomic changes were also observed in EPEC infected mice with changes in tricarboxylic acid (TCA) cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. The escN mutant colonized the mice with no weight loss or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.
Highlights
Gastroenteritis remains a major cause of morbidity and mortality in young children especially in developing countries (Liu et al, 2015)
The changes in body weight exhibited by individual Enteropathogenic E. coli (EPEC)-infected mice were correlated with their individual diarrhea scores at the overall peak of diarrhea and weight decrements on day 3 (Figure 1D), showing that higher diarrhea scores tended to associate with greater weight shortfalls
Typical EPEC infections have been suggested to be associated with inflammatory enteropathy and/or diarrhea in resource-limited populations (Platts-Mills et al, 2015; Rogawski et al, 2018)
Summary
Gastroenteritis remains a major cause of morbidity and mortality in young children especially in developing countries (Liu et al, 2015). Enteropathogenic E. coli (EPEC) has been recognized by the Global Enteric Multicenter Study (GEMS) and Malnutrition and Enteric Disease (MAL-ED) studies as one of the major causes of moderate to severe diarrhea in children (Kotloff et al, 2013; Platts-Mills et al, 2015). EPEC contains the locus of enterocyte effacement regulator (Ler) gene, a major transcriptional activator of LEE pathogenicity island, comprising around 41 open reading frames (Frankel et al, 1998; Friedberg et al, 1999). Typical EPEC are characterized by Localized Adherence (LA) in vitro (Kaper et al, 2004) and have been reported to cause severe diarrhea in children under 12 months of age and in certain cases results in death (Kotloff et al, 2013; Platts-Mills et al, 2015). Atypical EPEC is characterized by LA-like (Scaletsky et al, 2010), aggregative adherence or diffuse adherence in vitro (Pelayo et al, 1999; Mora et al, 2009) and are increasingly being detected in children worldwide (Abe et al, 2009; Hu and Torres, 2015)
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