Nuclease Expression by Staphylococcus aureus Facilitates Escape from Neutrophil Extracellular Traps

TLDR

Neutrophils defend against bacterial infection, and the discovery of neutrophil extracellular traps (NETs)—DNA scaffolds decorated with antimicrobial peptides, histones, and proteases—has revealed a key mechanism by which they kill pathogens, yet Staphylococcus aureus remains a leading human pathogen capable of systemic infection by evading effective neutrophil clearance. The study aimed to determine whether S. aureus nuclease facilitates NET degradation and contributes to virulence in a mouse respiratory infection model. Using targeted mutagenesis, the authors generated a nuclease‑deficient S.

Abstract

Neutrophils are key effectors of the host innate immune response against bacterial infection. <i>Staphylococcus aureus</i> is a preeminent human pathogen, with an ability to produce systemic infections even in previously healthy individuals, thereby reflecting a resistance to effective neutrophil clearance. The recent discovery of neutrophil extracellular traps (NETs) has opened a novel dimension in our understanding of how these specialized leukocytes kill pathogens. NETs consist of a nuclear DNA backbone associated with antimicrobial peptides, histones and proteases that provide a matrix to entrap and kill various microbes. Here, we used targeted mutagenesis to examine a potential role of <i>S. aureus</i> nuclease in NET degradation and virulence in a murine respiratory tract infection model. In vitro assays using fluorescence microscopy showed the isogenic nuclease-deficient (<i>nuc</i>-deficient) mutant to be significantly impaired in its ability to degrade NETs compared with the wild-type parent strain USA 300 LAC. Consequently, the <i>nuc</i>-deficient mutant strain was significantly more susceptible to extracellular killing by activated neutrophils. Moreover, <i>S. aureus</i> nuclease production was associated with delayed bacterial clearance in the lung and increased mortality after intranasal infection. In conclusion, this study shows that <i>S. aureus</i> nuclease promotes resistance against NET-mediated antimicrobial activity of neutrophils and contributes to disease pathogenesis in vivo.