Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis

Tirthankar Mohanty,Johan Malmström,Iben Lundgaard,Peter Reinstrup,Johan Bonnevier,Ariane Neumann,Christofer A Q Karlsson,Jane Fisher,José Francisco Pereira Cardoso,Adam Linder,Anahita Bakochi,Peter Bentzer,Chiara Pavan,Bo Nilson,David Cederberg

doi:10.1038/s41467-019-09040-0

Tirthankar Mohanty, Johan Malmström + Show 13 more

Open Access

https://doi.org/10.1038/s41467-019-09040-0

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Abstract

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Neutrophils release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures composed of decondensed DNA and neutrophil-derived antimicrobial proteins. Here we show NETs in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis, and their absence in other forms of meningitis with neutrophil influx into the CSF caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the CSF. Disrupting NETs using DNase I significantly reduces bacterial load, demonstrating that NETs contribute to pneumococcal meningitis pathogenesis in vivo. We conclude that NETs in the CNS reduce bacterial clearance and degrading NETs using DNase I may have significant therapeutic implications.

Highlights

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae
To examine the presence of neutrophil extracellular traps (NETs) in cerebrospinal fluid (CSF), cytospins from individuals afflicted with pneumococcal Acute bacterial meningitis (ABM), viral meningitis (VM), neuroborreliosis (NB) or subarachnoid hemorrhage (SH) were analyzed using immunofluorescence
NET formation in blood vessels is initiated by whole bacteria or bacterial products

Summary

Introduction

Neutrophils are crucial mediators of host defense that are recruited to the central nervous system (CNS) in large numbers during acute bacterial meningitis caused by Streptococcus pneumoniae. Acute bacterial meningitis (ABM) caused by Streptococcus pneumoniae (pneumococci) is a life-threatening medical condition that is accompanied by a high risk of debilitating neurological sequelae in survivors[1,2,3]. The primary function of the neutrophils is to rapidly engage and clear invading pathogens Neutrophils execute their function by phagocytosis, producing reactive oxygen species (ROS), hypochlorite and releasing antimicrobial protein/peptides through degranulation[7]. Neutrophils have been described to resist invading bacteria by secreting decondensed nuclear DNA coated with granule-derived antimicrobial proteins called neutrophil extracellular traps (NETs) into the external environment[10]. It was reported that short DNA fragments derived from the DNA-

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