An outbreak of neonatal diarrhoea was investigated in a herd of known susceptibility to infection by K88- positive Escherichia coli. The probable cause of the majority of diarrhoea cases was identified as a K88- positive E. coli strain. Diarrhoea was confined to susceptible piglets born to resistant sows. Susceptible sows protected their susceptible offspring and resistant piglets were unaffected. Potential protective mechanisms of the colostrum of susceptible sows were compared to the same properties in colostrum of resistant sows. Colostrum from susceptible sows (a) inhibited the binding of K88 antigen to intestinal epithelial cell brush borders, and (b) opsonized E. coli strain G205 and promoted in-vitro killing by porcine neutrophils significantly better than colostrum from resistant sows. Fractionation of colostrum by gel filtration and ion-exchange chromatography permitted identification of the immunoglobulin classes most efficient in both these activities. Both IgM and IgA, but not IgG, inhibited binding of K88 antigen to brush borders and opsonic activity was predominantly mediated by IgM. The importance of opsonic activity depends on the ab.ility of neutrophils to phagocytose bacteria within the intestinal lumen. In intestinal ligated loop experiments emigration of neutrophils into the lumen and phagocytosed bacteria were demonstrated by light microscopy and scanning and transmission electron microscopy. Neutrophil emigration only occurred when piglets had received maternal antibody_ No equivalent neutrophil emigration was observed in susceptible .piglets deprived of colostrum. There was also little or no neutrophil response in colostrum-fed resistant piglets probably du~ to a lower concentration of bacterial antigens close to the epithelial cell surface .or lack of specific antibody. Experiments to determine the numbers of organisms killed by neutrophils in the intestinal lumen failed to demonstrate any reduction, attributable to phagocytosis, in viable K88-positive E. coli.

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Infectious diseases represent one of the leading causes of death globally. Prompt diagnosis is essential for the onset of clinical treatment but certain cases of underlying bacterial infection deep in the body can remain undiagnosed for weeks. Hidden bacterial infection is the leading cause of fever of unknown origin (FUO), which is observed in 2 % of all hospital admissions around the world. Molecular imaging of bacterial infections is the ideal non-invasive diagnostic tool, but all available probes also detect inflammation. Two targets were selected for development of bacteria-specific molecular imaging probes, namely iron-uptake pathways and peptidoglycans involved in the synthesis of the cell wall. Both, Gram-positive and Gram-negative bacteria use iron-binding molecules called siderophores to scavenge iron from their surroundings. The structural similarities between Fe3+ and Ga3+ allow siderophores to be radiolabelled with 67/68Ga and visualized by nuclear medicine techniques. The clinically proven siderophore Deferoxamine (Dfo) has a plasma half-life of only 5.5 min that does not favor its direct use as a probe. Dfo derivatives with improved pharmacokinetics properties were designed and tested on Staphylococcus aureus cultures. The ciprofloxacin and the ethyloxycarbonyl derivatives of DFO at the primary amino position were among the most successful conjugates targeting the siderophore active-transport mechanism and reaching high relative uptake rates. Furthermore, the peptidoglycan pathway of Gram-positive bacteria was in vitro targeted with vancomycin conjugated to 67Ga-Dfo which showed even higher labelling capacity than 67Ga-Dfo within a few minutes of exposure. In vitro siderophore studies remain challenging due to the lack of methods for the preparation of rigorously iron-depleted media. We developed an iron chelating method with the goal of creating iron-free growth media. / Thesis / Master of Science (MSc)

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BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer. METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses. RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice. CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.

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