Dissecting the interaction between the EGF-R and IL33-R signalling pathway and its physiological relevance for resistance against bacterial lung infec

During inflammation cells of the immune system not only secrete a number of different cytokines but are also exposed to a number of different cytokines. Under different stages of inflammation, cells could thereby be exposed to a wide variety of different combinations of cytokines. Therefore each cell has to integrate a variety of external signals to ensure proper cell-fate decisions. The physiological relevance of different combinations of cytokines on the fate of immune cells has largely been overlooked so far, but may constitute a central mechanism by which an immune response can influence the specificity of the response it induces. Disregulation of immune responses can lead to the persistence of pathogens, tissue damage and auto-immune diseases.

We have found that two cytokine receptors, the Epidermal Growth Factor Receptor (EGF-R) and the Interleukin-33 Receptor (T1/ST2), physically interact with each other and are able to influence the physiological responses that the other receptor induces. As a result, fundamentally different responses are induced in target cells when both receptors are activated compared to when only one of them is activated. Both the IL-33- and EGF-receptors are highly expressed by aveolar macrophages, which are crucial for the clearance of bacterial lung infections. Therefore, our findings have direct physiological relevance and may potentially explain why cancer patients treated with EGF-R antagonists show an enhanced level of opportunistic infections, and many potentially explain why patients co-treated with EGF-R antagonists as well as with mTOR inhibitors can suffer of severe bacterial lung infections.

In this project, we will determine how on a molecular level the interaction of two cytokine receptors influence the specificity of the response induced in target cells. To this end, using a global proteomics approach, we will dissect the molecular mechanism by which a signal induced by one receptor influences the signal induced by the other receptor and how this interaction influences the physiological specificity of the induced signals. In parallel will we analyse the physiological relevance of this interaction, using in vivo model systems of bacterial lung infections.

Taken together, this project will combine the strength of proteomics with the expertise of molecular biological analysis of signal transduction and in vivo models of the therapeutic treatment of lung infections. It will address how the combination of cytokine release influence the specificity of immune responses and thus will open the opportunity to targeted influence immune responses in a therapeutic setting.