Human CFTR deficient iPSC-macrophages reveal impaired functional and transcriptomic response upon infection.

Introduction: Cystic fibrosis (CF) is a hereditary autosomal recessive disease driven by deleterious variants of the CFTR gene, leading, among other symptoms, to increased lung infection susceptibility. Mucus accumulation in the CF lung is, as of yet, considered as one important factor contributing to its colonization by opportunistic pathogens such as . However, in recent years evidence was provided that alveolar macrophages, which form the first line of defense against airborne pathogens, seem to be intrinsically defective with regard to bactericidal functionality in the CF lung. To assess the impact of CFTR deficiency in human macrophages only insufficient systems are available.

Methods: To address this problem and to evaluate the role of CFTR in human macrophages, we successfully differentiated human induced pluripotent stem cells (iPSC) from a CF p.Phe508del homozygous individual and a healthy donor into primitive macrophages (iMac and iMac), respectively, and compared the bactericidal functionality in the relevant cell type.

Results: iMac showed impaired clearance and intracellular killing capacity in comparison to iMac. Furthermore, iMac exhibited a less acidic lysosomal pH, and upon infection, there were signs of mitochondrial fragmentation and autophagosome formation together with a hyperinflammatory phenotype and deficient type I interferon response.

Conclusion: In summary, we present a defective phenotype in iMac upon infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF.