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Complement factor H contributes to mortality in humans and mice with bacterial meningitis

Title: Complement factor H contributes to mortality in humans and mice with bacterial meningitis
Authors: Kasanmoentalib, ES
Seron, MV
Engelen-Lee, JY
Tanck, MW
Pouw, RB
Van Mierlo, G
Wouters, D
Pickering, MC
Van der Ende, A
Kuijpers, TW
Brouwer, MC
Van de Beek, D
Item Type: Journal Article
Abstract: Background The complement system is a vital component of the inflammatory response occurring during bacterial meningitis. Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance. Methods In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in CFH influenced FH cerebrospinal fluid levels and/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (Cfh−/−) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model. Results We found the major allele (G) of single nucleotide polymorphism in CFH (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and Cfh−/− mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes. Conclusion Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.
Issue Date: 28-Dec-2019
Date of Acceptance: 16-Dec-2019
URI: http://hdl.handle.net/10044/1/82722
DOI: 10.1186/s12974-019-1675-1
ISSN: 1742-2094
Publisher: BioMed Central
Start Page: 1
End Page: 14
Journal / Book Title: Journal of Neuroinflammation
Volume: 16
Issue: 1
Copyright Statement: © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 212252/Z/18/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Neurosciences
Neurosciences & Neurology
Bacterial meningitis
Pneumococcal meningitis
Complement system
Complement factor H
Anti-inflammatory therapy
Animal models
TRANSLATIONAL MINIREVIEW SERIES
STREPTOCOCCUS-PNEUMONIAE
CEREBROSPINAL-FLUID
DISEASE
ADULTS
SUSCEPTIBILITY
ACTIVATION
CFH
PATHOPHYSIOLOGY
DEXAMETHASONE
Animal models
Anti-inflammatory therapy
Bacterial meningitis
Complement factor H
Complement system
Pneumococcal meningitis
Adult
Aged
Animals
Complement Factor H
Female
Humans
Male
Meningitis, Bacterial
Mice
Mice, Knockout
Middle Aged
Polymorphism, Single Nucleotide
Animals
Mice, Knockout
Humans
Mice
Meningitis, Bacterial
Complement Factor H
Polymorphism, Single Nucleotide
Adult
Aged
Middle Aged
Female
Male
Science & Technology
Life Sciences & Biomedicine
Immunology
Neurosciences
Neurosciences & Neurology
Bacterial meningitis
Pneumococcal meningitis
Complement system
Complement factor H
Anti-inflammatory therapy
Animal models
TRANSLATIONAL MINIREVIEW SERIES
STREPTOCOCCUS-PNEUMONIAE
CEREBROSPINAL-FLUID
DISEASE
ADULTS
SUSCEPTIBILITY
ACTIVATION
CFH
PATHOPHYSIOLOGY
DEXAMETHASONE
Neurology & Neurosurgery
1103 Clinical Sciences
1107 Immunology
1109 Neurosciences
Publication Status: Published
Article Number: ARTN 279
Online Publication Date: 2019-12-28
Appears in Collections:Department of Immunology and Inflammation
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons