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Mathematical modelling of immune cell host-pathogen interactions


Project Description

Mammals have central cellular defence systems that resist infection by a range of pathogens. These involve the NF-κB and STAT signalling systems, which we have shown to use dynamics and timing to encode pathogen-associated signals. We have recently developed novel imaging and genomics tools to study the direct interaction of immune cells with relevant pathogens at the single cell level. In particular we discovered that only a very small faction of the important food-borne bacterial pathogen Listeria monocytogenes could establish a successful infection of macrophages. These demonstrate that host cell and pathogen encounters are inherently dynamic and stochastic, leading to “seemingly” probabilistic infection outcomes in single cells. This raises fundamental questions about the host and pathogen inputs that regulate the intracellular fate of Listeria in macrophages, a key event in controlling infection.

From a theoretical point of view, single cell dynamics (and gene expression patterns) contain information about how cells process different threats and fight pathogen. The aim of the project is to use mathematical and statistical modelling to uncover how Listeria manipulates host cell signalling responses in order to successfully replicate and spread within infected population. In particular, we will develop new mathematical models of the NF-κB/STAT dynamics as well as microbial virulence systems in order to understand how different infection outcomes are controlled in single cells and cellular populations.

The highlight of the project is the collaboration with experimental scientists in the Systems Microscopy Centre (http://www.systemsmicroscopycentre.manchester.ac.uk ). This creates an opportunity to inform mathematical modelling with state-of-the-art live-cell imaging and single-cell genomics data collected in the group to gain unique insights into the single cell infection process.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in mathematics, engineering and computer science. Candidates interested in interdisciplinary systems biology research are encouraged to apply. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Standard band fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Radoshevich, L., Cossart, P., Listeria monocytogenes: towards a complete picture of its physiology and pathogenesis, Nature Reviews Microbiology, 2018, 16:32

Bagnall, J., Boddington, C., England, H., Brignall, R., Downton, P., Alsoufi, Z., Boyd, J., Rowe, W., Bennetts, A., Walker, C., Adamson, A., Patel, N., O'Cualain, R., Spiller, D., Jackson, D., Muller, W., Muldoon, M., White, M. & Paszek, P. “A quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation“, Science Signaling 2018 11:540

Adamson A, Boddington C, Rowe W, Bagnall JS, Downton P, Lam C, Schmidt L, Harper CV, Spiller DG, Rand DA, Jackson DJ, White MRH and Paszek P. “Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states”, Nature Communications 2016 7:12057

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