Introduction

AUTHOR=Rodriguez Gonzalez Claudio , Basílio-Queirós Débora , Neehus Anna-Lena , Merkert Sylvia , Tschritter David , Ünal Sinem , Hegermann Jan , Mörgelin Matthias , Bustamante Jacinta , Nietert Manuel Manfred , Martin Ulrich , Tümmler Burkhard , Munder Antje , Lachmann Nico TITLE=Human CFTR deficient iPSC-macrophages reveal impaired functional and transcriptomic response upon Pseudomonas aeruginosa infection JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1397886 DOI=10.3389/fimmu.2024.1397886 ISSN=1664-3224 ABSTRACT=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 Pseudomonas aeruginosa. 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^ΔF508 and iMac^WT), respectively, and compared the bactericidal functionality in the relevant cell type.

Results

iMac^ΔF508 showed impaired P. aeruginosa clearance and intracellular killing capacity in comparison to iMac^WT. Furthermore, iMac^ΔF508 exhibited a less acidic lysosomal pH, and upon P. aeruginosa 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^ΔF508 upon P. aeruginosa infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF.