PhD project

Supervisor: Emma Slack

The mammalian large intestine is home to several hundred bacterial species, forming the bacterial part of the intestinal microbiota, as well as being exposed to a vast array of xenoantigens via our food and to pathogenic bacteria, viruses and eukaryotic parasites. It is critical that the intestinal immune system does not overreact to harmless antigens, and yet that it does not ignore pathogenic threat. In contrast to what we know about adjuvants and antigens injected intramuscularly, the critical factors determining immunogenicity in the gut remain poorly understood. Understanding these concepts is critical for the design of oral vaccines and immunotherapies to prevent infectious and inflammatory diseases of the gastrointestinal tract.

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 bacterial reporter systems that is not degraded after bacterial death, are highly sensitive and can give spatially resolved information. In this project, we aim to track both highly resistant bacterial glycans and reporter systems based on lanthium-series ion-chelating proteins ² (CyTOF, imaging mass spectrometry) for oral antigens of different sizes, structures and compositions. Combined with the power of mouse genetics and microbiota manipulation, this project aims to uncover the structural and biochemical features of oral antigens that lead to robust samping into, and activation of, the intestinal immune system. 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 intestinally-delivered antigens ^4,5.

Publications:

• Schulz, O. & Pabst, O. Antigen sampling in the small intestine. Trends Immunol 34, 155–161 (2013).
• 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).
• Segers, A. & Depoortere, I. Circadian clocks in the digestive system. Nat Rev Gastroenterol Hepatol 18, 239–251 (2021).
• Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).
• Hoces, D. et al. Fitness advantage of Bacteroides thetaiotaomicron capsular polysaccharide is dependent on the resident microbiota. bioRxiv06.19.496708 (2022) doi:10.