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Rescue from Pseudomonas aeruginosa Airway Infection via Stem Cell Transplantation.

ABSTRACT: Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to impaired ion transport in epithelial cells. Although lung failure due to chronic infection is the major comorbidity in individuals with cystic fibrosis, the role of CFTR in non-epithelial cells has not been definitively resolved. Given the important role of host defense cells, we evaluated the Cftr deficiency in pulmonary immune cells by hematopoietic stem cell transplantation in cystic fibrosis mice. We transplanted healthy bone marrow stem cells and could reveal a stable chimerism of wild-type cells in peripheral blood. The outcome of stem cell transplantation and the impact of healthy immune cells were evaluated in acute Pseudomonas aeruginosa airway infection. In this study, mice transplanted with wild-type cells displayed better survival, lower lung bacterial numbers, and a milder disease course. This improved physiology of infected mice correlated with successful intrapulmonary engraftment of graft-derived alveolar macrophages, as seen by immunofluorescence microscopy and flow cytometry of graft-specific leucocyte surface marker CD45 and macrophage marker CD68. Given the beneficial effect of hematopoietic stem cell transplantation and stable engraftment of monocyte-derived CD68-positive macrophages, we conclude that replacement of mutant Cftr macrophages attenuates airway infection in cystic fibrosis mice.

SUBMITTER: Brinkert K

PROVIDER: S-EPMC7935663 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Rescue from Pseudomonas aeruginosa Airway Infection via Stem Cell Transplantation.

Brinkert Kerstin K Hedtfeld Silke S Burhop Annina A Gastmeier Rena R Gad Pauline P Wedekind Dirk D Kloth Christina C Rothschuh Justin J Lachmann Nico N Hetzel Miriam M Jirmo Adan Chari AC Lopez-Rodriguez Elena E Brandenberger Christina C Hansen Gesine G Schambach Axel A Ackermann Mania M Tümmler Burkhard B Munder Antje A

Molecular therapy : the journal of the American Society of Gene Therapy 20201203 3

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to impaired ion transport in epithelial cells. Although lung failure due to chronic infection is the major comorbidity in individuals with cystic fibrosis, the role of CFTR in non-epithelial cells has not been definitively resolved. Given the important role of host defense cells, we evaluated the Cftr deficiency in pulmonary immune cells by hematopoietic stem cell transplanta ...[more]

PMID: 33279724

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Project description:BackgroundThe respiratory tract epithelium is a critical environmental interface that regulates inflammation. In chronic infectious airway diseases, pathogens may permanently colonize normally sterile luminal environments. Host-pathogen interactions determine the intensity of inflammation and thus, rates of tissue injury. Although many cells become refractory to stimulation by pathogen products, it is unknown whether the airway epithelium becomes either tolerant or hypersensitive in the setting of chronic infection. Our goals were to characterize the response of well-differentiated primary human tracheobronchial epithelial cells to Pseudomonas aeruginosa, to understand whether repeated exposure induced tolerance and, if so, to explore the mechanism(s).MethodsThe apical surface of well-differentiated primary human tracheobronchial epithelial cell cultures was repetitively challenged with Pseudomonas aeruginosa culture filtrates or the bacterial media control. Toxicity, cytokine production, signal transduction events and specific effects of dominant negative forms of signaling molecules were examined. Additional experiments included using IL-1beta and TNFalpha as challenge agents, and performing comparative studies with a novel airway epithelial cell line.ResultsAn initial challenge of the apical surface of polarized human airway epithelial cells with Pseudomonas aeruginosa culture filtrates induced phosphorylation of IRAK1, JNK, p38, and ERK, caused degradation of IkappaBalpha, generation of NF-kappaB and AP-1 transcription factor activity, and resulted in IL-8 secretion, consistent with activation of the Toll-like receptor signal transduction pathway. These responses were strongly attenuated following a second Pseudomonas aeruginosa, or IL-1beta, but not TNFalpha, challenge. Tolerance was associated with decreased IRAK1 protein content and kinase activity and dominant negative IRAK1 inhibited Pseudomonas aeruginosa--stimulated NF-kappaB transcriptional activity.ConclusionThe airway epithelial cell response to Pseudomonas aeruginosa entails adaptation and tolerance likely mediated, in part, by down-regulation of IRAK1.

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Rescue from Pseudomonas aeruginosa Airway Infection via Stem Cell Transplantation.

Publications

Rescue from Pseudomonas aeruginosa Airway Infection via Stem Cell Transplantation.

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