Microbiome metabolites as immune checkpoints

The symbiotic relationship between the gut microbiota and host immune system promotes homeostasis and a balanced microbial ecosystem. Disruption of this cross talk can drive diseases like Inflammatory bowel disease (IBD) and colorectal cancer (CRC). Genetic, clinical and biological studies suggest malfunctioning of checkpoints that control the host-microbiome interface underlie disease (1). Our recent work has identified a novel role for the alpk1 gene in intestinal inflammation and CRC (2).

Alpha protein Kinase 1 (Alpk1) is a newly described kinase which acts as a cytosolic pattern recognition receptor for a bacterial metabolite ADP-heptose (ADPh), which is a derivative of  LPS biosynthesis (3). Mutations in ALPK1 are responsible for the ROSAH syndrome in humans, an autoinflammatory disease that can present with retinal pathology, childhood-onset arthritis, uveitis, and recurrent fever.

Utilising model systems of intestinal inflammation we demonstrate that Alpk1 plays a role in gut homeostasis following infection and immune challenge. In vivo approaches have shown that the metabolite ADPh suppresses Toll like Receptor  activation and cytokine production by mononuclear phagocytes suggesting this pathway is an important checkpoint shaping host microbial interactions to prevent tissue damaging inflammation.

The project combines the expertise of the Powrie lab in host microbe interactions and the Uhlig group  working with monogenic diseases and translational medicine approaches in intestinal diseases. The project will identify key pathways through which ADPh functions to regulate intestinal inflammation, determine its relevance in human systems and harness this knowledge to develop novel anti-inflammatory strategies.

Approach

1)    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. Impact on effector and regulatory T cell responses will be assessed (4). ADPh production in vivo including in gnotobiotic mice with synthetic microbial communities will be tracked using tissue mass spectrometry and visualised with imaging mass spectrometry.

2)    ALPK1 signalling

In vitro models composed of  mononuclear phagocytes  or epithelial organoids (mouse or human) will be used to identify signalling pathways down stream of ALPK1 that control the innate immune response (5). Specifically the ability of ADPh to rewire the MNP innate response to subsequent challenge will be tested. Identified protein pathways will be followed up using genetic targeting. Comparing gene deletion and gain-of-function patient derived variants will allow to understand the role of ALPK1 for host protective immunity and cyclical autoinflammation.

3)    Therapeutic Strategies

Information from 1 and 2 above will be used to generate novel therapeutic strategies that enhance anti-inflammatory pathways including testing novel chemical compounds based around the ADPh signalling pathway.           

KEYWORDS

Immunology, Inflammation, Microbiome, Metabolites, IBD (inflammatory bowel disease) 

TRAINING OPPORTUNITIES

This project offers exposure to cutting edge technologies including genomics, immunology, metabolism  and microbiome sciences. Training will be provided in mouse in vivo disease models, human tissue analysis, alongside immunology, imaging and bioinformatics. The PhD candidate will have the opportunity to interact with other PhD students/postdoc/PIs from the KIR or worldwide investigators through internal/external events.   

KEY PUBLICATIONS 

1. Uhlig HH, Powrie F. 2018 Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease. Annu Rev Immunol.;36:755-781.
2. Boulard, O., Kirchberger, S., Royston, D. J., Maloy, K. J. & Powrie, F. M. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. Journal of Experimental Medicine 209, (2012).
3. Zhou, P. et al. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561, (2018).
4. 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 April; 628, 854-862.

5.              Schulthess J, Pandey S, Capitani M, Rue-Albrecht KC, Arnold I, Franchini F, Chomka A, Ilott NE, Johnston DGW, Pires E, McCullagh J, Sansom SN, Arancibia-Cárcamo CV, Uhlig HH, Powrie F. 2019 The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages. Immunity 50(2):432-445.e7 

THEMES

Inflammation, Immunology, Microbiology, Translational Science 

CONTACT INFORMATION OF ALL SUPERVISORS

fiona.powrie@kennedy.ox.ac.uk

holm.uhlig@ndm.ox.ac.uk 

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025.

Applications should be made to the following programme using the specified course code.

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13th January 2025.