Frontiers in Immunology (Nov 2024)
Human CFTR deficient iPSC-macrophages reveal impaired functional and transcriptomic response upon Pseudomonas aeruginosa infection
- Claudio Rodriguez Gonzalez,
- Débora Basílio-Queirós,
- Anna-Lena Neehus,
- Anna-Lena Neehus,
- Anna-Lena Neehus,
- Anna-Lena Neehus,
- Anna-Lena Neehus,
- Sylvia Merkert,
- Sylvia Merkert,
- Sylvia Merkert,
- David Tschritter,
- Sinem Ünal,
- Sinem Ünal,
- Jan Hegermann,
- Jan Hegermann,
- Matthias Mörgelin,
- Jacinta Bustamante,
- Jacinta Bustamante,
- Jacinta Bustamante,
- Jacinta Bustamante,
- Manuel Manfred Nietert,
- Ulrich Martin,
- Ulrich Martin,
- Ulrich Martin,
- Burkhard Tümmler,
- Burkhard Tümmler,
- Antje Munder,
- Antje Munder,
- Nico Lachmann,
- Nico Lachmann,
- Nico Lachmann,
- Nico Lachmann,
- Nico Lachmann
Affiliations
- Claudio Rodriguez Gonzalez
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Débora Basílio-Queirós
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Anna-Lena Neehus
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Anna-Lena Neehus
- Paris Cité University, Imagine Institute, Paris, France
- Anna-Lena Neehus
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
- Anna-Lena Neehus
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
- Anna-Lena Neehus
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Sylvia Merkert
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, Hannover, Germany
- Sylvia Merkert
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Sylvia Merkert
- REBIRTH, Research Center for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany
- David Tschritter
- 0Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany
- Sinem Ünal
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Sinem Ünal
- Paris Cité University, Imagine Institute, Paris, France
- Jan Hegermann
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Jan Hegermann
- 1Research Core Unit Electron Microscopy, Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Matthias Mörgelin
- 2Colzyx AB, Lund, Sweden
- Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
- Jacinta Bustamante
- Paris Cité University, Imagine Institute, Paris, France
- Jacinta Bustamante
- 3Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris AP-HP, Paris, France
- Jacinta Bustamante
- 4St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
- Manuel Manfred Nietert
- 0Department of Medical Bioinformatics, University Medical Center Göttingen, Göttingen, Germany
- Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, Hannover, Germany
- Ulrich Martin
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Ulrich Martin
- REBIRTH, Research Center for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany
- Burkhard Tümmler
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Burkhard Tümmler
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Antje Munder
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Antje Munder
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Nico Lachmann
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- Nico Lachmann
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany
- Nico Lachmann
- REBIRTH, Research Center for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany
- Nico Lachmann
- 5Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- Nico Lachmann
- 6Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- DOI
- https://doi.org/10.3389/fimmu.2024.1397886
- Journal volume & issue
-
Vol. 15
Abstract
IntroductionCystic 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.MethodsTo 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 (iMacΔF508 and iMacWT), respectively, and compared the bactericidal functionality in the relevant cell type.ResultsiMacΔF508 showed impaired P. aeruginosa clearance and intracellular killing capacity in comparison to iMacWT. Furthermore, iMacΔF508 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.ConclusionIn summary, we present a defective phenotype in iMacΔF508 upon P. aeruginosa infection, which will constitute an ideal platform to further study the role of macrophages in the context of CF.
Keywords
