CFTR-dependent myeloid immune function and dysfunction in bacterial pneumonia/acute respiratory distress syndrome (ARDS)

• Applicant: Jonathan Gillan, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Clinical Immunology and Allergology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566108586

Loss-of-function mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) lead to cystic fibrosis (CF) and a variety of clinical symptoms affecting numerous parts of the body but predominantly the lungs. My previous work demonstrated that defective CFTR function in macrophages negatively affects their ability to mount an effective immune response. However impaired CFTR function is not just a problem for people with CF. We now know that in addition to hereditary mutations in CF, CFTR loss can also be acquired and occur in response to external stimuli, such as cigarette smoke and bacterial infections. Given that, I am interested in researching the clinical relevance of acquired CFTR defects, and consequent immune dysfunction, in macrophages in non-CF diseases. My proposed host lab, AG Kübler at the Institute of Physiology at Charité - Universitätsmedizin Berlin, has recently published findings showing that bacterial pneumonia causes acquired loss of CFTR in endothelial cells and this worsens the symptoms of pneumonia, including pulmonary edema and inflammation, as well as overall survival. I hypothesize that non-genomic, acquired loss of CFTR activity occurs in macrophages in the context of bacterial lung infection and that this is a substantial, and underappreciated, feature of the failure to resolve lung inflammation in non-CF, ARDS-causing bacterial pneumonia. Furthermore, I hypothesize that rescue of CFTR function in myeloid cells using CFTR modulator therapy contributes to improved host defense and aids resolution of neutrophilic inflammation in pneumonia/ARDS. The research program outlined below will investigate these hypotheses, with the following aims: 1. Assess the effect of bacterial pneumonia on CFTR expression and activity in lung myeloid cells. 2. Characterize the effect of reduced CFTR function on macrophage immune function and the resolution of bacterial inflammation in pneumonia models. 3. Investigate the potential of therapeutic CFTR potentiation of myeloid cells to bolster immune defense against pneumonia-associated lung inflammation and ARDS.

• DFG Programme: WBP Position