Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens

Abstract

The release of neutrophil extracellular traps (NETs) is a major immune mechanism intended to capture pathogens. These histone- and protease-coated DNA structures are released by neutrophils in response to a variety of stimuli, including respiratory pathogens, and have been identified in the airways of patients with respiratory infection, cystic fibrosis, acute lung injury, primary graft dysfunction, and chronic obstructive pulmonary disease. NET production has been demonstrated in the lungs of mice infected with Staphylococcus aureus, Klebsiella pneumoniae, and Aspergillus fumigatus. Since the discovery of NETs over a decade ago, evidence that "NET evasion" might act as an immune protection strategy among respiratory pathogens, including group A Streptococcus, Bordetella pertussis, and Haemophilus influenzae, has been growing, with the majority of these studies being published in the past 2 years. Evasion strategies fall into three main categories: inhibition of NET release by down-regulating host inflammatory responses; degradation of NETs using pathogen-derived DNases; and resistance to the microbicidal components of NETs, which involves a variety of mechanisms, including encapsulation. Hence, the evasion of NETs appears to be a widespread strategy to allow pathogen proliferation and dissemination, and is currently a topic of intense research interest. This article outlines the evidence supporting the three main strategies of NET evasion-inhibition, degradation, and resistance-with particular reference to common respiratory pathogens.

Keywords: Streptococcus; deoxyribonuclease; immune evasion; neutrophil extracellular traps.

Figure 1.

Neutrophil extracellular trap (NET) release. (1) Upon stimulation by a variety of triggers, including many pathogens, neutrophils release NETs into the extracellular space. (2) These structures are composed of DNA coated with histones and chromatin, and trap microbes in a concentrated environment of antimicrobial proteins, such as neutrophil elastase and myeloperoxidase. Insets are images showing (left) human NETs released by phorbol myristate acetate–stimulated neutrophils by fluorescence microscopy using Sytox Green (arrows), and (right) green-stained Salmonella typhimurium bacteria (arrows) trapped in murine NETs. (3) As well as exerting antimicrobial effects, NETs may play a proinflammatory role contributing to the pathogenesis of conditions, such as acute lung injury and venous thromboembolism.

Figure 2.

The three main NET evasion strategies. Certain respiratory pathogens have evolved the ability to evade the antimicrobial effects of NETs, using three main mechanisms: inhibition of the release of NETs; degradation of NETs by the production of pathogen nucleases; and resistance to the effects of the antimicrobial proteins that are enmeshed within NETs.