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Nuclease Expression by Staphylococcus aureus Facilitates Escape from Neutrophil Extracellular Traps

2010; Karger Publishers; Volume: 2; Issue: 6 Linguagem: Inglês

10.1159/000319909

1662-8128

Evelien T.M. Berends, Alexander R. Horswill, Nina M. Haste, Marc Monestier, Victor Nizet, Maren von Köckritz‐Blickwede,

Immune Response and Inflammation

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.