Dataset Information

Neutrophil extracellular traps in the central nervous system: a novel therapeutic target in pneumococcal meningitis.

ABSTRACT: Neutrophils are crucial mediators of host defense and are recruited to the central nervous system in large numbers during acute bacterial meningitis caused by S. pneumoniae. Neutrophils can release neutrophil extracellular traps (NETs) during infections to trap and kill bacteria. Intact NETs are fibrous structures and mainly consist of decondensed DNA and neutrophil-derived antimicrobial proteins. We report the extensive presence of NETs in the cerebrospinal fluid of patients with pneumococcal meningitis, and absence of NETs in other forms of meningitis caused by viruses, Borrelia and subarachnoid hemorrhage. In a rat model of meningitis, a clinical strain of pneumococci induced NET formation in the cerebrospinal fluid. Importantly, disrupting NETs using DNase I significantly reduced bacterial load, demonstrating that NETs contribute to the pathogenesis of pneumococcal meningitis in vivo. Targeting NETs using DNase may represent a novel indication for an already approved drug as a non-antibiotic therapeutic option to treat acute pneumococcal meningitis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Streptococcus Pneumoniae Tigr4

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Meningitis

SUBMITTER: Christofer Karlsson

LAB HEAD: Johan Malmström

PROVIDER: PXD011546 | Pride | 2019-11-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Anahita_H1701_024.pep.xml	Pepxml
	Anahita_H1701_024.raw	Raw
	Anahita_H1701_025.pep.xml	Pepxml
	Anahita_H1701_025.raw	Raw
	Anahita_H1701_026.pep.xml	Pepxml

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Publications

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

Mohanty Tirthankar T Fisher Jane J Bakochi Anahita A Neumann Ariane A Cardoso José Francisco Pereira JFP Karlsson Christofer A Q CAQ Pavan Chiara C Lundgaard Iben I Nilson Bo B Reinstrup Peter P Bonnevier Johan J Cederberg David D Malmström Johan J Bentzer Peter P Linder Adam A

Nature communications 20190410 1

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, an ...[more]

PMID: 30971685

Similar Datasets

Project description:Meningitis is a life-threatening condition characterized by the inflammation of the leptomeningeal membranes surrounding the brain and spinal cord. The term meningitis is an umbrella term and includes several different etiologies. The majorities of meningitis cases are caused by viruses (viral meningitis; VM) and are often associated with low mortality rates and low risk of developing neurological. In contrast, meningitis caused by some viral infections, such as tick-borne encephalitis (TBE), can be life-threatening when left untreated with increased risk of developing neurological sequelae. Acute bacterial meningitis (ABM), however, is one of the leading causes of death due to infectious diseases worldwide and is associated with rapid disease progression, high mortality rates and increased risk of long-term neurological sequelae in survivors. As meningitis is caused by numerous different pathogens, the host-response is typically highly variable and it is currently unknown if different pathogens can introduce specific proteome changes in the cerebrospinal fluid (CSF). In this study we applied DIA-MS to provide novel insights for in-depth understanding of central nervous system functioning and host response during meningitis in a cohort of patients with differential diagnosis of meningitis, to account for variability contributed by different disease-causing pathogens. The results reveal drastic changes in the CSF proteome during meningitis, where in particular a massive increase of neutrophil derived proteins in the CSF correlated with ABM, suggesting that activated neutrophils play a particular role in ABM. Additionally both ABM and VM result in marked reduction of brain-specific proteins in the CSF, which could be indicative of pathophysiological mechanisms leading to brain damage. Furthermore, generation of lasso regression model enables separation of ABM with high sensitivity and specificity, demonstrating that several proteins are required to confidently discriminate between ABM, VM and BM.