The role of AhR in sensing infection dynamics
The host immune system is well equipped to detect potential pathogens. I recently discovered that the Aryl hydrocarbon Receptor (AhR) directly recognises bacterial pigmented virulence factors, such as Pseudomonas aeruginosa (P. aeruginosa) phenazines (Moura-Alves, P. et al, Nature 2014). This indicates that AhR, a molecule that until recently has primarily been studied in the context of toxicology, plays a crucial role in regulating host immunity to infection. Upon binding a phenazine, the AhR elicits diverse immune responses and coordinates host resistance to infection. P. aeruginosa phenazines are part of the Quorum Sensing (QS) system, a cell-to-cell communication system used by bacteria to coordinate their gene expression in response to changes in their population density, or infection stage. Therefore, if a host sensor can detect these different molecules and their expression patterns, it may allow hosts to customise their immune responses according to the stage of infection. Because of its capability to detect a vast number of endogenous and exogenous metabolites, we consider that the AhR is suitable to recognise different bacterial molecules expressed at various stages of infection, thereby shaping immune response accordingly. However, the elicited host responses might lead to fundamental changes in the bacterial community, whereby an adaptation to a new scenario might pose a new paradigm to the host that also needs to be evaluated.
The aim of the laboratory is to study the role of the AhR as a host sensor and modulator of bacterial communication and infection dynamics, together with its importance in shaping immune responses which are appropriate to the infection stage. Thus, the key objectives are:
1) Evaluate the role of the AhR in sensing different molecules expressed at various stages of bacterial growth and infection.
2) Evaluate the impact of the host AhR elicited responses on bacterial adaptation strategies.
3) Dissect the AhR interactome during infection and its impact on host defence mechanisms.
Connections in the AhR: a ticket to multiple destinations, including immune responses to infection and Cancer. The AhR might serve as an “airport” that, under different circumstances, deals with the arrival of diverse cargos that need to be identified and directed to their correct destinations. During infection, by changing the expression of different molecules (cargos), bacteria might present to the AhR the cues that the host uses to identify different infection stages. Upon recognition of these cargos, the AhR rapidly mobilises its network and assigns the different protocols or functions to be taken, therefore leading to distinct outcomes/destinations, including different immune responses and bacterial adaptation strategies. In a similar fashion, the AhR might play an important role in regulating host responses to cancer by sensing different tumour metabolic profiles during the course of the disease. The main research aims are depicted with respective numbers inside yellow boxes. Yellow circles depict the main interactions to be studied.
We employ a wide range of existing state-of-the-art techniques to evaluate how the host AhR senses infection dynamics and how it impacts bacterial community responses. In addition, we are developing and implementing new tools to allow real time monitoring of host immune activation patterns and bacterial adaptation strategies, both in vitro and in zebrafish larvae, allowing us to monitor infection dynamics from both sides of the war simultaneously. By uncovering the mechanisms that allow hosts and bacteria to spy on each other, this work will open up new possibilities for the development of novel therapies to control bacterial infections, according to not only the type of infection but also to the infection stage. Considering AhR as a potential host-directed therapy (HDT) target, this work might lead to important breakthroughs in the treatment of bacterial infections, as well as other diseases where AhR plays a role, including cancer.
The Role of the AhR in sensing Tumour microenvironment and cancer dynamics
Recent evidence suggests that the AhR plays an important role in diverse types of cancer, such as lung, skin, liver and breast cancer. It has been shown that the AhR is involved in diverse stages of tumorigenesis, including initiation, progression, invasion and metastasis. Therefore, in collaboration with other research groups at the Ludwig, we aim to expand our initial studies on infection to dissect the role of the AhR in sensing the tumour microenvironment and cancer dynamics.