Connecting in-vivo optical imaging with dynamic modelling of host-pathogen interaction during bacterial infection

点击翻译按钮获取中文摘要

Bacterial infections are experienced by almost everyone at least once during their lifetime. Although antibiotic treatments will cure the infection in most cases, bacteria are constantly developing and can become resistant to antibiotics. This way, new strains of bacteria continue to emerge, including strains that have considerable costs in terms of morbidity and mortality. Multiple outbreaks of aggressive forms of E.coli in recent years have demonstrated that these types of bacteria are not completely under control. For these bacteria we need to develop appropriate treatments, which can only be done if we understand how bacteria establish infections.To find out how a bacterial infection evolves in the body over time, we should investigate this process inside living animals, such as mice, that can represent the course of human disease. Recently, new imaging systems have been developed that can track bacteria inside a mouse without any invasive intervention. This is achieved by using bacteria that emit light at a wavelength larger than the visible range, which can travel through several centimetres of tissue; enough for the light of bacteria in the gut to reach the surface of the animal. It is also possible to use a fluorescent probe inside the mouse to visualize other cells that are important for the immune response of the mouse. With this technique we can see where the bacteria and immune cells are in the body, how many there are, and by imaging at multiple time points, we can also follow their movement. The precision with which we can locate cells in the body is of the order of millimetres.In order to be able to interpret the large-scale in-vivo images in terms of the small-scale infection mechanisms, we need to link what we can observe with what we know about the infection based on other investigations. These other investigations include detailed post-mortem investigations of separate organs that show exactly where the bacteria are located; for example, whether bacteria are attached to the wall of the gut, or whether they have moved beyond it.In this project, we will develop techniques and tools that allow us to combine in-vivo image analysis with the available biological knowledge at the cellular and molecular scale. The project includes theoretical modelling of the progress of bacterial infection with deterministic and stochastic methods, as well as experimental in-vivo imaging of bioluminescent bacteria inside a mouse. The modelling work will be performed within the Theoretical Systems Biology group, while the experimental work will be performed within the Molecular Pathogenesis group, both at Imperial College London. By interweaving theoretical modelling with experimental investigation of the disease model, we will be able to feedback theory into experimental design, and experimental results into the definition of the model; both are equally important in order to arrive at good mechanistic models for the infection processes. The model we will thus obtain of the progress of bacterial infection can deliver new insights across spatial and temporal scales and potentially help identify new targets for treatment.