AhR(port) dynamics: dissecting the Aryl hydrocarbon Receptor interactome during the course of infection

Project Overview

Figure 1- Connections in the AhR: a ticket to multiple destinations, including immune responses to ...

Background

I have previously uncovered a role of the Aryl hydrocarbon Receptor (AhR) as a host sensor of infection, involved in the direct recognition of Pseudomonas aeruginosa and Mycobacterium tuberculosis molecules (Moura-Alves, P.et al, Nature, 2014). Notably, we demonstrated that the AhR is of extreme importance for different host defense functions, culminating in increased resistance to infection. In sum, we unveiled an AhR role as an innate immune sensor, demonstrating that this ligand-activated transcription factor can serve as a Pattern Recognition Receptor (PRR) involved in sensing pathogen associated molecular patterns (PAMPs), leading to the induction of specific transcriptional programs.

Nevertheless, AhR’s modus operandi in the context of infection might not be restricted to transcription. Host-signaling pathways do not occur in an independent and isolated fashion within cells, and crosstalk between these pathways plays important roles in shaping the final outcome. During bacterial infection, multiple signaling pathways can be triggered simultaneously, or sequentially, depending for example on the localization of a specific host sensor in the cell, the expression of different bacterial molecules or the infection stage. Therefore, it is of great importance to dissect the existing crosstalk among these pathways, their regulation, and ultimately their impact on the outcome of bacterial infections. 

Aim

The main aim of this project is to evaluate these existing crosstalk(s) and their impact on AhR mediated immune responses to bacterial infections. We will evaluate the AhR interactome during infection, focusing initially on the crosstalk with signaling pathways known to play important roles in the regulation of inflammation and immune responses to infection (e.g. NF-kB, Hypoxia inducible factor 1α (Hif-1α), Figure 1).

         Research objectives

              - Dissect the AhR interactome during infection.

              - Identify the mechanisms by which AhR modulates other signaling pathways during infection

              - Implement an in vivo zebrafish larvae model to visualize the existing crosstalks during infection.

              - Develop a methodology to study individual/synergistic impact of diverse signaling pathways in host

              defence to infection.

Training Opportunities

Training Opportunities

During this project you will use in vitro and in vivo models, including cell lines, bacteria and zebrafish larvae. You will have the opportunity to develop multiple cell and zebrafish lines using CRISPR-Cas9 technology, as well as diverse signalling reporters. Moreover, you will make use of diverse state-of-the-art techniques, such as RNAseq, Metabolomics and Proteomics.

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 1017

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Pedro Moura Alves Oxford Ludwig Institute Oxford University, NDM Research Building GBR pedro.mouraalves@ludwig.ox.ac.uk
Professor Mads Gyrd-Hansen Oxford Ludwig Institute Oxford University, Old Road Campus Research Building GBR mads.gyrd-hansen@ludwig.ox.ac.uk

Moura-Alves P, Faé K, Houthuys E, Dorhoi A, Kreuchwig A, Furkert J, Barison N, Diehl A, Munder A, Constant P, Skrahina T, Guhlich-Bornhof U, Klemm M, Koehler AB, Bandermann S, Goosmann C, Mollenkopf HJ, Hurwitz R, Brinkmann V, Fillatreau S, Daffe M, Tümmler B, Kolbe M, Oschkinat H, Krause G, Kaufmann SH. 2014. AhR sensing of bacterial pigments regulates antibacterial defence. Nature, 512 (7515), pp. 387-92. Read abstract | Read more

The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns. Hide abstract