title: Enteroaggregative Escherichia coli strain in a novel weaned mouse model: exacerbation by malnutrition, biofilm as a virulence factor and treatment by nitazoxanide.
abstract: Enteroaggregative Escherichia coli (EAEC) is increasingly recognized as a common cause of diarrhoea in healthy, malnourished and immune-deficient adults and children. There is no reproducible non-neonatal animal model for longitudinal studies of disease mechanism or therapy. Using two strains of human-derived EAEC to challenge weaned C57BL/6 mice, we explored an in vivo model of EAEC infection in mice, in which disease was monitored quantitatively as the growth rate, stool shedding and tissue burden of organisms; nutritional status was varied, and a new class of therapeutics was assessed. A single oral challenge of EAEC strain 042 resulted in significant growth shortfalls (5-8 % of body weight in 12 days), persistent shedding of micro-organisms in stools [>10(3.2) c.f.u. (10 mg stool)(-1) for at least 14 days] and intestinal tissue burden [~10(3) c.f.u. (10 mg tissue)(-1) detectable up to 14 days post-challenge]. Moderate malnourishment of mice using a 'regional basic diet' containing 7 % protein and reduced fat and micronutrients heightened all parameters of infection. Nitazoxanide in subMIC doses, administered for 3 days at the time of EAEC challenge, lessened growth shortfalls (by >10 % of body weight), stool shedding [by 2-3 logs (10 mg stool)(-1)] and tissue burden of organisms (by >75 % in the jejunum and colon). Thus, weaned C57BL/6 mice challenged with EAEC is a convenient, readily inducible model of EAEC infection with three highly quantifiable outcomes in which disease severity is dependent on the nutritional status of the host, and which is modifiable in the presence of inhibitors of pyruvate ferredoxin oxidoreductase such as nitazoxanide.
authors.affiliation: Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Bolick
authors.affiliation: Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Roche
authors.affiliation: Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA.
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.affiliation: Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
authors.affiliation: Department of Pediatrics, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Nataro
authors.affiliation: Center for Global Health, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
mesh_terms: D000818:Animals; D018441:Biofilms / Q000254:growth & development; D003106:Colon / Q000382:microbiology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology*; D005243:Feces / Q000382:microbiology; D006801:Humans; D008297:Male; D044342:Malnutrition / Q000150:complications*; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds; D013844:Thiazoles / Q000627:therapeutic use*; D014774:Virulence; D037521:Virulence Factors; D014886:Weaning
chemical_list: D009574:Nitro Compounds; D013844:Thiazoles; D037521:Virulence Factors; C041747:nitazoxanide