CFZEBRA · Balancing the immune response in cystic fibrosis: using zebrafish models of infection and inflammation to uncover new therapeutic approaches

Balancing the immune response in cystic fibrosis: using zebrafish models of infection and inflammation to uncover new therapeutic approaches

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). In people with CF, the defect in CFTR gene causes a severe defect of mucociliary clearance with the development of thick mucus, which forms a protected niche for bacterial growth, resulting in chronic infection and high-intensity inflammation. These factors conspire to damage the lungs leading to extensive morbidity and early death. In addition to known mucociliary defects, several lines of evidence have shown that CFTR dysfunction causes intrinsic alterations in epithelial and innate immune cell responses to tissue injury and pathogens, creating a vicious circle of infection and dysregulated inflammation. Currently, there is no cure for CF and the evaluation of biological function of CFTR in available CF models suffers from several limitations, predominantly the evaluation of phenomena in a pre-existing inflammatory environment. Consequently, the mechanisms by which CFTR directly regulates innate immunity and how CF mutations contribute to infectious and inflammatory pathogenesis in CF have remained obscure. There is therefore a pressing need to develop models allowing direct observation of CFTR-dependent effects on innate immune responses in the absence of pre-existing inflammatory environment. Zebrafish innate immunity is closely homologous to that of humans, while their optical transparency allows non-invasive, real-time monitoring of infectious and inflammatory processes in the whole organism. Importantly, zebrafish CFTR retains close sequence identity with human. Like mammals, zebrafish CFTR is expressed in epithelial surfaces and myeloid cells and plays an important role in homeostatic balance of fluid composition. The high degree of genetic and functional conservation between the zebrafish and mammalian CFTR and innate immune systems make zebrafish a clinically-relevant system to investigate CF immune-pathophysiology. The overall objective of this project is to understand how CFTR dysfunction leads to abnormal inflammation and innate immunity in CF using CFTR-mutant zebrafish larvae as an innovative vertebrate model of inflammation and infection, combined with human CF stem cell approaches, in ways that are not possible in other models systems. To achieve this objective, the project is focus on 3 different research themes: a) Generate and validate new models of CFTR dysfunction. b) Define the host innate immune response to infection and sterile tissue injury in CF models. c) Screen for anti-inflammatory / pro-resolution drugs with a potential role in re-balancing the immune responses. The main goal of this action was to develop an innovative approach using new models in the search of strategies for mimicking the innate immune abnormalities of CF to find new avenues for increasing the understanding on deleterious immunity in CF and to deliver better therapeutic approaches to the clinic.

Data: CORDIS, © European Union