Project Portugal 2030

Summary

Bacterial adaptation strategies are a major cause of persistent infections and antibiotic resistance[5]. QS is an important mechanism allowing bacterial communities to rapidly adapt to new environments, resulting for example from host-mediated responses during infection[5,6]. Consequently, studies assessing P.aeruginosa QS regulation, and QS-related adaptation strategies during infection, should not be performed dissociated from the host. Similarly, as P.aeruginosa QS impacts the host, this constant adaptation ultimately alters host responses, which need to be studied concomitantly. Thus, in contrast to studies focused on single “snapshots” in time, with defined and fixed cellular and bacterial conditions, we will address this existing complexity and monitor the continuous and coexisting adaptive processes in host and bacteria simultaneously. As such, we will gain a novel spatiotemporal resolution of their interaction during infection and identify key players from both sides of this crosstalk. We discovered that the AHR acts as a PRR recognizing bacterial ligands, as P.aeruginosa QSSMs, and modulating the response to infection[8,9]. Therein, we have shown that infection with P.aeruginosa mutants expressing different levels of QSSMs, or bacteria collected at diverse growth phases, renders different AHR modulation (Fig.1)[9]. Further, AHR KO mice infected with P.aeruginosa are more or less resistant to infection compared to WT, depending on the growth phase at which bacteria were inoculated[9]. Therefore, if AHR can detect these molecules and their expression patterns throughout infection, it may allow hosts to customize their immune responses accordingly. Furthermore, we have shown that the AHR is implicated in the degradation of some QSSMs by host cells, and preliminary data shows that AHR ligands can impact the expression of QSSM by P.aeruginosa (Fig.2,4). The outcome of this “arms race” results from the dynamic interplay between the host responses and the related pathogen countermeasures. In other terms, the elicited host responses might lead to important changes in the bacteria community, and the bacterial adaptation might pose a new paradigm to the host that also needs to adapt. This proposal aims to study both sides of this “war” simultaneously, dissecting 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 appropriate to the infection stage. Ultimately, this multidisciplinary and innovative experimental approach might lead to new therapeutic interventions. Thus, the key objectives of this proposal are: 1) Evaluate the role of the AHR in sensing different molecules expressed at various stages of bacterial infection. We will systematically dissect the AHR roles in sensing and responding to infection dynamics, upon recognition of diverse molecules expressed at different stages of infection. 2) Evaluate the impact of the host AHR-elicited responses on P.aeruginosa adaptation strategies. We will evaluate whether the expression of diverse QSSMs, and QS-related mechanisms are influenced by the expression of AHR and its mediated responses. 3) Evaluate how the AHR-QS crosstalk impacts infection dynamics and potential therapeutic interventions. We will evaluate whether the AHR and QS receptors sense similar molecular cues, thereby instructing host and bacteria co-adaptation strategies, with a potential impact on therapy.