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.

Keywords: IFN-β; IFNAR; NETs; Pseudomonas aeruginosa; bacterial infection; biofilms; innate immunity; neutrophils.