Detrimental Effect of Type I IFNs During Acute Lung Infection With Pseudomonas aeruginosa Is Mediated Through the Stimulation of Neutrophil NETosis.

Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Pylaeva, Ekaterina;
ORCID
0000-0002-8766-3135
Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Bordbari, Sharareh;
Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Spyra, Ilona;
Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Decker, Anna Sophie;
ORCID
0000-0001-6141-9102
Affiliation
Molecular Bacteriology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
Häussler, Susanne;
Affiliation
Institute for Astronomy and Astrophysics, Eberhard Karls University, Tübingen, Germany.
Vybornov, Vadim;
GND
1163226122
LSF
47359
Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Lang, Stephan;
GND
1047129906
LSF
58530
Affiliation
Translational Oncology, Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany.
Jablonska, Jadwiga

Pseudomonas aeruginosa is an opportunistic multidrug-resistant pathogen, able to grow in biofilms. It causes life-threatening complications in diseases characterized by the up-regulation of type I interferon (IFN) signaling, such as cancer or viral infections. Since type I IFNs regulate multiple functions of neutrophils, which constitute the first line of anti-bacterial host defense, in this work we aimed to study how interferon-activated neutrophils influence the course of P. aeruginosa infection of the lung. In lungs of infected IFN-sufficient WT mice, significantly elevated bacteria load was observed, accompanied by the prominent lung tissue damage. At the same time IFN-deficient animals seem to be partly resistant to the infection. Lung neutrophils from such IFN-deficient animals release significantly lower amounts of neutrophil extracellular traps (NETs) and reactive oxygen species (ROS), as compared to WT neutrophils. Of note, such IFN-deficient neutrophils show significantly decreased capacity to stimulate biofilm formation by P. aeruginosa. Reduced biofilm production impairs in turn the survival of bacteria in a lung tissue. In line with that, treatment of neutrophils with recombinant IFN-β enhances their NETosis and stimulates biofilm formation by Pseudomonas after co-incubation with such neutrophils. Possibly, bacteria utilizes neutrophil-derived NETs as a scaffold for released biofilms. In agreement with this, in vivo treatment with ROS-scavengers, NETs disruption or usage of the bacterial strains unable to bind DNA, suppress neutrophil-mediated biofilm formation in the lungs. Together, our findings indicate that the excessive activation of neutrophils by type I IFNs leads to their boosted NETosis that in turn triggers biofilm formation by P. aeruginosa and supports its persistence in the infected lung. Targeting these mechanisms could offer a new therapeutic approach to prevent persistent bacterial infections in patients with diseases associated with the up-regulation of type I IFNs.

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Pylaeva, E., Bordbari, S., Spyra, I., Decker, A.S., Häussler, S., Vybornov, V., Lang, S., Jablonska Jablonska-Koch, J., 2019. Detrimental Effect of Type I IFNs During Acute Lung Infection With Pseudomonas aeruginosa Is Mediated Through the Stimulation of Neutrophil NETosis. https://doi.org/10.3389/fimmu.2019.02190
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