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

Abstract

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.

Type I Interferon-Mediated Regulation of Antiviral Capabilities of Neutrophils

“…In a positive feedback loop, these traps—which are composed primarily of DNA, high mobility group box protein 1 (HMGB1), and the cathelicidin antimicrobial peptide LL37—subsequently activate pDCs, which in turn produce more IFN-α via DNA binding to TLR9 [ 84 ]. Interferon-deficient mice have reduced production of NETs and reactive oxygen species (ROS), while recombinant IFN-β treatment restored NETosis [ 85 ]. Controlling this feedback loop may be a method warranting further examination in diseases that are exacerbated by excessive formation of NETs.…”

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

“…Another therapeutic target related to NETs formation is Type I interferon. A recent finding suggests that Type I interferon-driven NETosis may promote respiratory P. aeruginosa infections in mice by providing a scaffold to support biofilm production [86]. Interruption of interferon signaling may, therefore, be useful for suppressing infection by biofilm-capable organisms, but care would need to be taken not to increase susceptibility to viral infection.…”

Pseudomonas Aeruginosa Induced Cell Death in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Infections with bacteria, such as P. aeruginosa , are often linked to the increase in type I IFN signaling in lung epithelial cells [ 47 ]. It has been demonstrated that type I IFN-mediated activation of neutrophils in lungs causes increase in NETosis, leads to the prominent tissue damage, and supports biofilm formation by P. aeruginosa and its persistence in the lung [ 48 ]. The role of PH in mediation of NETosis is also an important aspect [ 49 ].…”