Perinatal dysfunction of innate immunity in cystic fibrosis

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, <i>CFTR</i> transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

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Publication Details

Journal
Science Translational Medicine
Published
2025-01-22
DOI
https://doi.org/10.1126/scitranslmed.adk9145
Citations
7
Primary Topic
Cystic Fibrosis Research Advances
Type
article
Field-Weighted Citation Impact
10.63
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article

Perinatal dysfunction of innate immunity in cystic fibrosis

Karl Kunzelmann, Florian Bartenschlager, Thomas Fröhlich, Stefan Krebs et al.
7 citations
Science Translational Medicine
Cystic Fibrosis Research Advances
10.63
article

Perinatal dysfunction of innate immunity in cystic fibrosis

Karl Kunzelmann, Florian Bartenschlager, Thomas Fröhlich, Stefan Krebs, Lars Mundhenk, Ignacio Caballero, Nora Naumann‐Bartsch, Eckhard Wolf, Armin Saalmüller, Bachuki Shashikadze, Andrea Bähr, Nikolai Klymiuk, Gianluca Santamaria, Johannes Berges, Dorota Zawada, Michael Stirm, Cornelia A. Deeg, Marcus Alexander Mall, Alexander Schnell, Karl‐Ludwig Laugwitz, Josep M. Cambra, Christian Kupatt, Simon Y. Graeber, Alessandra Moretti, Heiko Bruns, Jan B. Stöckl, Florian Jaudas, Roxane L. Degroote, Monika Stefańska, Helmut Blum, Melanie Janda, Wilhelm Gerner, Daniel Reichart, Christian Schulz, Huan Liu, Heike Kartmann, Lea Hanselmann
article en
7 citations

Abstract

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, <i>CFTR</i> transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

Science Translational MedicineVol. 17(782)
Université de Tours (FR), University of Veterinary Medicine Vienna (AT), University of Mannheim (DE), Heidelberg University (DE), University Hospital Heidelberg (DE), LMU Klinikum (DE), Magna Graecia University (IT), Humboldt-Universität zu Berlin (DE), Universitätsklinikum Erlangen (DE), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Gene Therapy Laboratory (FR), Institute of Bioinformatics and Systems Biology (DE), Physiologie de la Reproduction et des Comportements (FR), Biologie des oiseaux et aviculture (FR), German Centre for Cardiovascular Research (DE), Services déconcentrés d'appui à la recherche Val de Loire (FR), German Center for Lung Research (DE), Deutsches Herzzentrum München (DE), University Medical Centre Mannheim (DE), Urologische Klinik München (DE), University of Regensburg (DE), Technical University of Munich (DE), Freie Universität Berlin (DE), Ludwig-Maximilians-Universität München (DE)
Openalex Percentile: Top 2%
Cystic Fibrosis Research Advances
10.63
DOISourceOpenAlex
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