Unpicking the infection puzzle: experimental design

Theme: World-Class Underpinning Bioscience

In many infections, cells that take up bacteria (macrophages) play a key role in preventing bacterial growth and spread. Our preliminary experimental results show that when a macrophage is infected by the food poisoning bacterium Salmonella, those cells stiffen by stabilizing the cytoskeletal protein F---actin. This appears to prevents the uptake of further bacteria and stops the cell moving, which would halt spread of infection around the body.

We think the molecular mechanism invovles bacterial detection by a host pathogen recognition receptor which activates an effector protein called caspase 1. In the Bryant lab, experimentalists are generating data to explore this hypothesis using macrophages that lack either the pattern recognition receptor or the effector proteins. The data support a role for the receptor in instigating changes in the mechanical properties of the cell after infection, but the data is confusing with respect to the effector enzyme protein caspase 1. Usually cells lacking caspase 1 are softer. However upon infection, cells lacking casapse 1 become stiffer which is the reverse of what would be expected. So, what might be an important cellular mechanism for containing infection at the host level is poorly understood. But we have the possibility of further experiments, but these must be carefully targeted.

The aim of this project is to generate potential models to explain this conundrum in experimental data which can then be tested experimentally. This will require dialogue with experimentalists (in the Bryant lab) and also likely require advanced mathematics and/or computation to build appropriate models. The existing mathematical modeling literature here is very underdeveloped, so on the one hand there is a wide open area, but on the other hand, it will require real innovation early in the PhD, rather than following a well---trodden path.