Mouse models help scientists understand E. coli infections in babies

In infants and young children, the bacterium E. coli (Escherichia coli) causes serious disease, including diarrhea, fever, vomiting, dehydration, and even death. Scientists have now found a way to reproduce symptoms of a form of E. coli called EPEC (Enteropathogenic E. coli) in infected mice, so they can study how the disease develops.

In the past, scientists studying E. coli have used infected animals, like pigs and mice, to try and understand the disease.  If the symptoms seen in humans could be accurately reproduced in animals, this could be the key to developing new vaccines or treatments. Unfortunately, so far, scientists have found it difficult to recreate all the symptoms of the infection exactly as they appear in humans. 

In this study, researchers wanted to produce the same E. coli symptoms seen in children suffering from EPEC in infected mice.  Some of the most important symptoms of interest were diarrhea, slower growth and development, inflammation, and intestinal damage. Theys also wanted to test how a genetic change to the bacteria would affect the symptoms the mice developed.

Initially, researchers treated the mice with a course of antibiotics to kill off some of their existing gut bacteria, allowing the E. coli bacteria to develop and grow more easily.  They then infected the mice with either normal, unchanged EPEC, or with EPEC that had been genetically modified to be less efficient at infecting intestinal cells. They compared these mice to a group of healthy, uninfected mice.  With the mice divided into their groups, the researchers monitored them for growth and symptoms of disease.

Mice that had been infected with normal EPEC grew more slowly than uninfected mice, and they developed diarrhea exactly as human infants would. The researchers also found the same chemical “markers” of infection in the mice that are seen in children. Infected mice also had damage to their intestines and showed signs that they weren’t able to produce enough energy to meet their needs – a fact the researchers believe partly explains weight loss during E. coli infection.  

Meanwhile, the mice infected with the genetically modified EPEC lost less weight, had fewer overall signs of infection, and also had no intestinal damage, even though they still carried the bacteria.

In previous studies, scientists had difficulty producing certain symptoms in mice, like diarrhea. Being able to reproduce these symptoms of EPEC in a natural setting, inside the intestines, is an important step forward. This mouse model can help researchers understand exactly how symptoms develop in EPEC infections, which would ultimately help scientists develop better therapeutics to prevent or treat these symptoms.

In the long run, this may lead to the development of better treatments or even vaccines that can improve health outcomes for children in developing countries. The study was a collaboration between researchers from South Africa, Brazil, the UK and the USA.

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 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, but had no weight changes 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 many 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.

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