The disease severity in cystic fibrosis (CF) is determined both by the type of CFTR mutation but also by modifier genes present in the individual genetic profile. How modifier genes influence disease mechanisms and individual response to pharmacological treatments remains to be established. We exploited a new mouse model called Collaborative Cross (CC) with mutation Cftr-F508del, generated in our laboratory. Differently from previous models, CC models are characterized by a heterogeneous genetic profile and mimic the genetic diversity of the human population. Our data indicate that the same Cftr-F508del mutation in the context of different genetic profiles affects prenatal and postnatal survival. To date, the temporal and causal relationship between inflammation and pulmonary infection in humans remains unclear and we showed that the respiratory inflammatory response, characterized by an increase in infiltrating neutrophils and monocytes, is established at a very early age and before infection. Measurement of biomarkers of inflammation and tissue damage – cytokines/chemokines, myeloperoxidase, and elastase – confirm the presence of this very early respiratory phenotype associated with the Cftr-F508del mutation. The pulmonary phenotype correlates with systemic inflammation and severe intestinal pathology indicating a possible link between the gut and pathology in other organs in the early stages of the disease. Thus, pharmacological treatments that resolve intestinal pathology also attenuate systemic and pulmonary inflammation.

Our study suggests that host genetic background may influence the development of currently unidentified disease phenotypes and open new hypotheses on the disease. The development of these new mouse models is expected to facilitate progress toward a more detailed understanding of CF pathogenesis and support translational studies to the human population. In particular, research efforts focused on extrapulmonary organs are instrumental in the era in which highly effective therapies with CFTR modulators are significantly improving pulmonary manifestations.

Abstract

• Sipione B, Lorè N, Rossi G et al. F508-CFTR mutation in genetically diverse collaborative cross mice expands CF disease-relevant phenotypes. North American Cystic Fibrosis Conference, November 2 – 5, 2021, Fully Virtual 2021
• Sipione B, Lorè NI, Rossi G et al. F508del-CFTR in genetically diverse collaborative cross mice yield cystic fibrosis phenotypes. North American Cystic Fibrosis Conference, October 7 – 23, 2020 
• Genomic characterization of a novel mouse model of ΔF508-CFTR in genetically-diverse collaborative cross background, North American Cystic Fibrosis Conference, October 7 – 23, 2022, D’Aurora M, Sipione B, Colombi F et al.