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Age-dependent host factors and the site of gastrointestinal translocation in Escherichia coli K1 neonatal systemic infection

Dalgakiran, F; (2015) Age-dependent host factors and the site of gastrointestinal translocation in Escherichia coli K1 neonatal systemic infection. Doctoral thesis , UCL (University College London).

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Abstract

Escherichia coli K1 is a major cause of neonatal bacterial meningitis (NBM). Mortality and morbidity of NBM remains significant, requiring new treatments to alleviate the disease burden. Our understanding of many aspects of disease pathogenesis has been acquired through the use of a robust neonatal rat model of E. coli K1 systemic infection. Translocation of E. coli K1 from the GI tract into the blood compartment is a key step in the disease progression that is poorly understood. Knowledge of the key mechanisms underlying the age-dependent susceptibility of the neonates to E. coli K1 could identify novel therapeutic targets. Using the neonatal rat model, this study aimed to analyse 1) the spatial distribution of E. coli K1 in the GI tract in an attempt to identify the site of translocation, 2) the role of Paneth cells in E. coli K1 pathogenesis and 3) the possibility of endogenous Trefoil factor 2 (Tff2) feeding as a prophylactic therapy. Evidence was found suggesting that the middle small intestine of susceptible animals may be the site where E. coli K1 translocates into the bloodstream by a transcellular route. Susceptible animals were unable to control E. coli K1 numbers at the site of translocation. Two thirds of the resistant animals became susceptible to E. coli K1 infection when their antimicrobial peptide (α-defensins) producing Paneth cells were selectively ablated with a chemical reagent, dithizone. Daily feeding of recombinant Tff2 (a protein that promotes mucin layer maturation) to susceptible animals reduced the incidence of bacteraemia and increased survival by approximately 30%. These results indicate that the E. coli K1 systemic infection is a multi-factorial process. Enhancement of the GI tract barrier in two-day-old animals at the site of translocation with recombinant Tff2 or α-defensins represents a potential strategy for the prophylaxis of neonatal E. coli K1 infection.

Type: Thesis (Doctoral)
Title: Age-dependent host factors and the site of gastrointestinal translocation in Escherichia coli K1 neonatal systemic infection
Event: UCL (University College London)
Language: English
Keywords: E. coli K1, neonatal bacterial meningitis, E. coli K1 systemic infection, E. coli K1 pathogenesis, Trefoil factor 2 (Tff2), Paneth cells, spatial distribution of E. coli K1, site of translocation
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: http://discovery.ucl.ac.uk/id/eprint/1472000
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