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(WIS) How food-borne Listeria monocytogenes overcomes the host defence mechanisms at the single cell level?


Project Description

Pathogens have developed intricate ways to overcome the host’s immune system. In this proposal we will study the direct interaction of macrophages with the important food-borne bacterial pathogen Listeria monocytogenes that causes significant human morbidity and mortality. Our data demonstrate that encounters between host cells and pathogens are inherently dynamic and stochastic, leading to “seemingly” probabilistic infection outcomes in single cells. 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. This raises fundamental questions about the host and pathogen interactions that determine the intracellular fate of Listeria in macrophages, a key event in controlling infection.

The aim of the project is to use cutting-edge single cell biology approaches to understand and predict outcomes of single-cell host-pathogen interactions. For the first time we will quantitatively investigate key signalling events that occur in single cells in response to pathogen infection, and simultaneously monitor pathogen behaviour and the activation of the host immune response. The project will focus on the role of the NF-B dynamics, key host defence signalling system a and the action of microbial virulence genes in controlling immune responses to infection in single cells. Together we will develop a novel, quantitative understanding of how Listeria manipulates the host cell signalling responses in order to replicate successfully and propagate infection. This has a potential to identify new host defence strategies, which in the future, could assist with the treatment of infectious disease.

The highlight of the project is the collaboration between world leading groups at the University of Manchester, UK and Weizmann Institute of Science, Israel to develop unprecedented insight into the single-cell infection process. Training in novel and topical imaging and single-cell biology approaches will be provided to fit the student’s interests and complement their existing skills. In addition to excellent academic record, the ideal candidate should have great communications skills and interests in interdisciplinary research.

Entry Requirements
Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors honours degree or equivalent in a relevant subject area.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Weizmann Institute of Science, as outlined on 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

Avraham, R., N. Haseley, D. Brown, C. Penaranda, H. B. Jijon, J. J. Trombetta, R. Satija, A. K. Shalek, R. J. Xavier, A. Regev and D. T. Hung (2015). "Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses." Cell 2015 162(6): 1309-1321

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

White, E. C., Houlden, A., Bancroft, A. J., Hayes, K. S., Goldrick, M., Grencis, R. K. & Roberts, I. S., Manipulation of host and parasite microbiotas: Survival strategies during chronic nematode infection 2018, I: Science Advances. 2018: 4, 3

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