Role of Innate lymphoid cells (ILC) and aryl hydrocarbon receptor (AhR) during pulmonary bacterial infections

• Applicant: Professorin Chiara Romagnani, Ph.D.
• Subject Area: Immunology
• Term: from 2016 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320429054

Pulmonary diseases caused by Pseudomonas aeruginosa (P.aer) represent one major cause of hospitalization and mortality, especially in immunocompromised individuals and in patients affected by cystic fibrosis. Intratracheal infection with P.aer can be used to study the acute immune response and inflammation, which is mainly mediated by the innate immune system, especially neutrophils, and spontaneously resolved within 96 h, together with complete bacterial clearance. IL-17 responses allegedly contribute to neutrophil recruitment and resistance against P.aer; however the sources of this cytokine as well as the role of lung innate lymphoid cells (ILCs) during P.aer infection remain unclear. S. Kaufmann (the Co-PI of this project during the first funding period) had shown that the aryl hydrocarbon receptor (AhR) acts as a recognition sensor for pigmented virulence factors from P.aer, and that impairment in AhR signalling affects bacterial load, host survival and tissue damage during in vivo infection. However, the immunological mechanisms responsible for this effect have only started to be elucidated. As AhR signalling is crucial in modulating differentiation and functions of T cells and ILCs, we aimed to investigate the role of AhR signalling and ILCs during P.aer infection.In the previous funding period, we have characterized ILC responses after in vivo intratracheal infection with P.aer and assessed the impact of conditional AhR deletion in different lymphocyte lineages. We could show that lung ILC3 and NKp46+ ILCs cells are both activated during in vivo infection with P.aer. However, while RORt-dependent lymphocytes, including ILC3, are dispensable for survival, selective deletion of AhR signalling in NKp46+ ILCs has a severe impact in the late survival and disease course after P.aer infection.Based on this data, we hypothesised that NKp46+ ILC may play a role in the late regulation of immunopathology, following P.aer infection. To test this hypothesis, in the next funding period, we aim to uncover the role of NKp46+ ILCs during P.aer infection and define the cell intrinsic signatures established by AhR signalling in these cells. This project will enable us unveiling the understudied role of ILCs during pulmonary bacterial infections and possibly help to identify new targets for the modulation of acute inflammation and tissue damage.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells