
handle: 10616/40053
The pathological outcome of a bacterial infection depends on the interplay between the host s defences and the virulence arsenal of the pathogen. Appreciation of this interplay is crucial to the understanding of pathogenesis and the development of efficient clinical treatments. In this thesis we wanted to study the dynamics of the early stages of renal bacterial infection. While sacrificial models and in vitro experimentation has given us a wealth of information, they lack the spatial and temporal resolution required to follow the crucial first hours of infection. To overcome this we developed a multiphoton based live animal infection model which allows for the visualization of infection progression in real-time. This model allows for cellular resolution visualisation of events occurring in the live kidney with the influences of the all physiological factors such as the blood, nervous, hormonal and immune systems intact. Our model utilizes micropuncture techniques to directly infuse bacteria into the renal tubules allowing for a well defined time-frame of infection. What we achieved was a unique insight into the rapid physiological responses to infection. Physiological responses described in this thesis include ischemic and obstruction injuries. These injuries are both related to dynamic physiological functions for which real-time live imaging is particularly suitable. Within 3-4 hours of the first bacterial interaction, epithelial signalling lead to activation of the clotting cascade and shut-down of local peri-tubular capillaries. The clotting response was shown to be crucial to isolate the infection and prevent sepsis. A rapid and dramatic drop in local tissue oxygen tension was also recorded with the combination resulting in a local ischemic injury. This infection-induced ischemia resulted in the characteristic cellular actin and integrin re-arrangements, but lacked a re-perfusion stage, instead resulting in localised tissue damage. We also investigated the effect of bacterial infection on renal filtration, ...
570, Thesis, 610
570, Thesis, 610
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