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Novel insights into bacterial sampling by the intestinal immune system


   Sir William Dunn School of Pathology

  Prof Emma Slack  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

The mammalian large intestine is home to several hundred bacterial species, forming the bacterial part of the intestinal microbiota. Yet only a fraction of these species elicits a mucosal immune response. The factors underlying immunogenicity in the gut remain poorly understood but are clearly disrupted in intestinal disorders such as Crohn’s disease and innate immunodeficiencies. Understanding these concepts is also critical for the design of oral vaccines and immunotherapies.

Sampling of antigen from the gut lumen into gut-draining lymph nodes is the first step in induction of any mucosal immune response1. Currently this can only be directly observed using highly artificial in vitro or surgically isolated systems. To study real sampling dynamics in vivo, we critically lack good tools. Sampled bacteria are rare and rapidly killed, therefore we need to build a bacterial reporter system that is not degraded after bacterial death, is highly sensitive and can give spatially resolved information.

Lanmodulin2, and other lanthium series ion-chelating proteins provide a potential solution. Lanthium series metals are very rare in intestinal microbes and tissues, are relatively non-toxic and can be easily detected by plasma-coupled mass spectrometry, CyTOF and imaging mass cytometry. In this project, you will design and test systems for over-expression and controlled expression of Lanmodulin in E.coli, Salmonella and Bacteroides species. We will also test strategies to load different isotopes in vitro, in vivo and ex vivo. Pathway engineering and directed evolution approaches will be used to improve uptake of relevant ions and to maximize Lanmodulin expression while minimizing toxicity. The overall aim is to allow robust single-cell-level detection of intestinal bacteria in gut-associated lymphoid tissues. These bacterial reporters will then be applied to probe the fundamental biology of intestinal antigen sampling. Specifically, we can investigate how bacterial factors (viability, aggregation, surface structures, oxygen-tolerance and abundance), microbiome composition, and host factors (activity of pattern-recognition receptors, epithelial integrity, circadian rhythm3, intestinal motility, IgA specificity etc) influence the rate of uptake, cellular targets and degradation rates of bacterial antigens 4,5


Funding Notes

4 Year DPhil Prize Studentships cover University fees, a tax free stipend of ~£20,168 pa, and up to £5,300 pa for research costs and travel. The competition is open to applicants from all countries. See View Website for full details and to apply.

References

1. Schulz, O. & Pabst, O. Antigen sampling in the small intestine. Trends in Immunology 34, 155–161 (2013).
2. Cotruvo, J. A., Featherston, E. R., Mattocks, J. A., Ho, J. v. & Laremore, T. N. Lanmodulin: A Highly Selective Lanthanide-Binding Protein from a Lanthanide-Utilizing Bacterium. J Am Chem Soc 140, 15056–15061 (2018).
3. Segers, A. & Depoortere, I. Circadian clocks in the digestive system. Nature Reviews Gastroenterology and Hepatology 18, 239–251 (2021).
4. Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).
5. Hoces, D. et al. Fitness advantage of Bacteroides thetaiotaomicron capsular polysaccharide is dependent on the resident microbiota. bioRxiv 2022.06.19.496708 (2022) doi:10.1101/2022.06.19.496708.

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