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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1508727

Human Airway Epithelium Controls Pseudomonas aeruginosa Infection via inducible Nitric Oxide Synthase

Provisionally accepted
Philipp Grubwieser Philipp Grubwieser 1,2Nina Boeck Nina Boeck 3Erika Kvalem Soto Erika Kvalem Soto 3Richard Hilbe Richard Hilbe 1Patrizia Moser Patrizia Moser 4Markus Seifert Markus Seifert 1Stefanie Dichtl Stefanie Dichtl 2Miriam Alisa Govrins Miriam Alisa Govrins 2Wilfried Posch Wilfried Posch 2Thomas Sonnweber Thomas Sonnweber 1Manfred Nairz Manfred Nairz 1Igor Theurl Igor Theurl 1Zlatko Trajanoski Zlatko Trajanoski 3*Günter Weiss Günter Weiss 1,5*
  • 1 Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
  • 2 Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
  • 3 Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
  • 4 INNPATH, Innsbruck Medical University Hospital, Innsbruck, Austria
  • 5 Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Tyrol, Austria

The final, formatted version of the article will be published soon.

    Airway epithelial cells play a central role in the innate immune response to invading bacteria, yet adequate human infection models are lacking. We utilized mucociliary-differentiated human airway organoids with direct access to the apical side of epithelial cells to model the initial phase of Pseudomonas aeruginosa respiratory tract infection. Immunofluorescence of infected organoids revealed that Pseudomonas aeruginosa invades the epithelial barrier and subsequently proliferates within the epithelial space. RNA sequencing analysis demonstrated that Pseudomonas infection stimulated innate antimicrobial immune responses, but specifically enhanced the expression of genes of the nitric oxide metabolic pathway. We demonstrated that activation of inducible nitric oxide synthase (iNOS) in airway organoids exposed bacteria to nitrosative stress, effectively inhibiting intraepithelial pathogen proliferation. Pharmacological inhibition of iNOS resulted in expansion of bacterial proliferation whereas a NO producing drug reduced bacterial numbers. iNOS expression was mainly localized to ciliated epithelial cells of infected airway organoids, which was confirmed in primary human lung tissue during Pseudomonas pneumonia. Our findings highlight the critical role of epithelial-derived iNOS in host defence against Pseudomonas aeruginosa infection. Furthermore, we describe a human tissue model that accurately mimics the airway epithelium, providing a valuable framework for systemically studying host-pathogen interactions in respiratory infections.

    Keywords: airway organoids, Pseudomonas aeruginosa, iNOS, Airway epithelia, innate immunity

    Received: 09 Oct 2024; Accepted: 05 Nov 2024.

    Copyright: © 2024 Grubwieser, Boeck, Kvalem Soto, Hilbe, Moser, Seifert, Dichtl, Govrins, Posch, Sonnweber, Nairz, Theurl, Trajanoski and Weiss. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Zlatko Trajanoski, Biocenter, Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Tyrol, Austria
    Günter Weiss, Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.