About the Project
The intestinal microbiome is a complex community of organisms that exists in symbiosis with its host. Microbiota perform essential digestive, metabolic, and immunomodulatory functions in health, and disturbance of the microbiota can contribute to disease. Microbial metabolites are a key ingredient in healthy host-microbe dialogue, bolstering barrier immunity and immune regulatory pathways. Our recent work on microbiota-derived small molecule metabolites such as ADP-heptose has identified new immune regulatory and microbicidal functions that could be targeted in inflammatory bowel disease. However, harnessing metabolites as disease therapeutics has been challenging because of their diverse cellular targets and the complex bacterial community ecology governing their production and function.
ADP-L-glycero-b-D-manno-heptose (ADP-heptose) is an LPS intermediate that is sensed by the intracellular kinase Alpha Protein Kinase 1 (ALPK1) leading to activation of TRAF-interacting protein with forkhead associated domain (TIFA) and the NF-kB pathway. Additional heptoses, CDP-heptose and UDP-heptose made by mammalian cells also bind ALPK1 and activate TIFA/NF-kB signalling, although little is known about the functional consequences of these interactions. Human genetic mutations in ALPK1 influence binding of specific heptoses and are associated with autoinflammatory disease.
This project will i) identify key pathways through which nucleoside heptoses condition innate immunity and shape barrier surface immunity, ii) determine their relevance in human systems and iii) harness this knowledge to develop novel anti-inflammatory strategies.
Approach
- Functional role of ADPh - In vivo models using cell type specific Alpk1 deficient mice will be used to identify key cell types and immune/infection challenges controlled by ADPh sensing.
- ALPK1 signalling - In vitro models using monoclear phagocytes (MNP) or epithelial organoids (mouse or human) will be used to identify signalling pathways down stream of ALPK1 that control the innate immune response. Specifically the ability of ADPh, CDPh UDPh to rewire the MNP innate response to further challenge will be tested. Identified protein pathways will be followed up using genetic targeting.
- Therapeutic Utility - Information from 1 and 2 above will be used to generate therapeutic strategies that enhance anti-inflammatory pathways including testing novel chemical compounds and assessment of signalling in monogenic patients with ALPK1 mutations.
This project will take a multi-disciplinary approach, using immunology, biochemistry, imaging, microbial ecology and gnotobiology.
KEYWORDS:
Immunology, intestine, metabolites, microbiome, biochemistry
TRAINING OPPORTUNITIES:
This project offers exposure to cutting edge technologies including genomics, immunology, metabolism and microbiome sciences. The training will be provided in mouse in vivo disease models and human immunology alongside immunology, imaging and bioinformatics. The PhD candidate will have the opportunity to interact with other PhD students/postdoc/PIs from KIR or worldwide investigators through internal/external events.
THEMES:
Inflammation, Immunology, Microbiology, metabolism
CONTACT INFORMATION OF ALL SUPERVISORS:
- Fiona.powrie@kennedy.ox.ac.uk
- Holm.uhlig@well.ox.ac.uk
- Claire.pearson@kennedy.ox.ac.uk
- Alice.bertocchi@kennedy.ox.ac.uk
PROJECT CODE: KIR-NC-13/KIR-Clinical-10/KIR-AfOx-07
References
Gu Y, Bartolomé-Casado R, Xu C, Bertocchi A, Janney A, Heuberger C, Pearson CF, Teichmann SA, Thornton EE, Powrie F. Immune microniches shape intestinal Treg function. Nature. 2024 Apr;628(8009):854-862. doi: 10.1038/s41586-024-07251-0. Epub 2024 Apr 3. PMID: 38570678; PMCID: PMC11041794.
Uhlig, H. H. & Muise, A. M. Clinical Genomics in Inflammatory Bowel Disease. Trends in Genetics vol. 33 (2017).
Ryzhakov G, West NR, Franchini F, Clare S, Ilott NE, Sansom SN, Bullers SJ, Pearson C, Costain A, Vaughan-Jackson A, Goettel JA, Ermann J, Horwitz BH, Buti L, Lu X, Mukhopadhyay S, Snapper SB, Powrie F. Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis. Nat Commun. 2018 Sep 18;9(1):3797. doi: 10.1038/s41467-018-06085-5. PMID: 30228258; PMCID: PMC6143560.
Boulard O, Kirchberger S, Royston DJ, Maloy KJ, Powrie FM. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. J Exp Med. 2012 Jul 2;209(7):1309-24. doi: 10.1084/jem.20120239. Epub 2012 Jun 25. PMID: 22734048; PMCID: PMC3405508.
Lequain et al. ROSAH syndrome: childhood-onset arthritis, hand deformities, uveitis, and splenomegaly. The Lancet Rheumatology 5, (2023).
