U037657.pdf (69.93 MB)
Disease mechanism of enteropathogenic escherichia coli.
thesisposted on 2015-11-19, 08:53 authored by Thomas John. Baldwin
Colonization of gut mucosal surfaces by enteropathogenic Escherichia coli (EPEQ elicits a severe persistant diarrhoea in infants and young children without elaboration of enterotoxins or tissue invasion. The formation of a distinct ultrastructural lesion involving intimate adherence to cell surfaces, loss of microvilli and membrane perturbations, however, has for some time been recognized as an important component of pathogenesis, but the processes involved in lesion formation and its relevance to the disease state remained obscure. In this study intimate adherence of EPEC to surfaces of cultured cells has been shown to elicit specific changes reminiscent of cellular activation by various hormones and growth factors via signal transduction pathways. The formation of two second messengers, 1,4,5-inositol trisphosphate and diacylglycerol by the activity of phospholipase C (PLC) on membrane phosphatidylinositol lipids is known to promote release of calcium from intracellular stores and to activate protein kinase C (PKC) respectively. Therefore the observed intracellular calcium elevation, calcium-dependent actin accretion at sites of bacterial attachment, release of glycosyl-phosphatidylinositol (GPI) anchored proteins, eventual loss of host cell viability, and phosphorylation of target cell proteins on EPEC infection of cultured cells, are consistent with a mechanism of diarrhoeagenesis that involves activation of a host cell signal transduction pathway terminating in PLC activity. I propose that the rapid onset of severe secretory diarrhoea associated with EPEC infections is induced by phosphorylation of particular ion transport proteins in the microvillus membrane, mediated by calcium-dependent kinases and PKC. In addition reduction in the surface area of infected regions of the gut, which may itself enhance hypersecretion by preventing absorption, can be explained by calcium-dependent breakdown of the microvillus cytoskeleton.
Date of award1990-01-01
Awarding institutionUniversity of Leicester