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Are metabolites generated by the microbiota key to a young immune system? (#202010)

About This PhD Project

Project Description

By 2050, the world’s population aged >60 years is expected to be 2 billion, up from 900 million in 2015, a major concern for the individual and for society. One of the contributing factors is ageing of the immune system. Aged individuals are less efficient at fighting infections and malignancies, have reduced capacity to respond to vaccinations. The mission of our ageing research is not to improve life span but health span, i.e. to reduce the burden of age-related diseases. Evidence is emerging that just a handful of cellular processes malfunctioning with age underlie these diseases. One of these processes is autophagy, the main mechanism by which cells remove cellular waste. Over the years, we have demonstrated a role for autophagy in different types of immune cells 1 2. We found that autophagy declines with age in immune cells. Cells start to accumulate material that cannot be digested, which stops them from executing their function and they produce inflammatory cytokines in excess. When we induce autophagy with the polyamine spermidine, immune cells are rejuvenated, in particular memory CD8+ T cells 3 and B cells. Subsequently we uncovered a novel molecular pathway that controls autophagy downstream of polyamines. It involves the translation factor eIF5A and transcription factor TFEB 4.

A major source of polyamines is the gut microbiota. It is known that gut bacteria are able to modulate host metabolism and immunity through the release of metabolites. In humans, the core microbiome is significantly different between old and young but the key metabolites maintaining a healthy lifespan have not been identified. In this DPhil project, we will determine the metabolites from young and old and address if autophagy and thereby immune responses are maintained by the metabolites produced by gut bacteria. In close collaboration with Justin and Erica Sonnenburg (Stanford, CA, US) we will genetically engineer gut bacteria to overproduce polyamines or other identified metabolites that differ between young and old 5. We will use these to test if the eIF5A/ TFEB pathway, autophagy and immune responses can be recovered. There is an increasing interest in using microorganisms as probiotics, either in fermented dairy products or formulated as tablets. However, convincing scientific data supporting their health claims are scarce. This study will help to understand at the metabolite level how the microbiome contributes to ageing.

Training Opportunities

Training will be provided in techniques including genetically engineering of gut microbiota, defining the metabolome (and related bioinformatics), and immunological techniques such as multi parameter flow cytometry, histochemistry, confocal microscopy. You will attend regular seminars within the department and in the wider University. You will be expected to present data regularly in lab meetings and in departmental progress report seminars and in national and international conferences. You will have the opportunity to work closely with collaborating groups interested in the microbiome (Fiona Powrie, KIR and Justin and Erica Sonnenburg, Stanford, CA, US). Ghada Alsaleh, senior postdoc in the lab, will take on daily supervision. A core curriculum of lectures is offered in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis, statistics and the microbiome.

Key Publications

Riffelmacher, T., Clarke, A., Richter, F. C., Stranks, A., Pandey, S., Danielli, S., Hublitz, P., Yu, Z. R., Johnson, E., Schwerd, T., McCullagh, J., Uhlig, H., Jacobsen, S. E. W. & Simon, A. K. Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity 47, 466-480, doi:10.1016/j.immuni.2017.08.005 (2017).

Clarke, A. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells Nature Reviews Immunology, doi:10.1038/s41577-018-0095-2 (2018).

Puleston, D. J., Zhang, H., Powell, T. J., Lipina, E., Sims, S., Panse, I., Watson, A. S., Cerundolo, V., Townsend, A. R., Klenerman, P. & Simon, A. K. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 3, doi:10.7554/eLife.03706 (2014).

Zhang, H., Alsaleh, G., Feltham, J., Sun, Y., Napolitano, G., Riffelmacher, T., Charles, P., Frau, L., Yu, Z., Mohammed, S., Ballabio, A. Balabanov, S., Mellor, J., Simon, A.K. Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence. Molecular Cell 76, 1-16, doi:10.1016/j.molcel.2019.08.005 (2019).

Whitaker, W. R., Shepherd, E. S. & Sonnenburg, J. L. Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut Microbiome. Cell 169, 538-546 e512, doi:10.1016/j.cell.2017.03.041 (2017).

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