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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Meningitis | Research

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

Authors: E. Soemirien Kasanmoentalib, Mercedes Valls Serón, Joo Yeon Engelen-Lee, Michael W. Tanck, Richard B. Pouw, Gerard van Mierlo, Diana Wouters, Matthew C. Pickering, Arie van der Ende, Taco W. Kuijpers, Matthijs C. Brouwer, Diederik van de Beek

Published in: Journal of Neuroinflammation | Issue 1/2019

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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.
Appendix
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Metadata
Title
Complement factor H contributes to mortality in humans and mice with bacterial meningitis
Authors
E. Soemirien Kasanmoentalib
Mercedes Valls Serón
Joo Yeon Engelen-Lee
Michael W. Tanck
Richard B. Pouw
Gerard van Mierlo
Diana Wouters
Matthew C. Pickering
Arie van der Ende
Taco W. Kuijpers
Matthijs C. Brouwer
Diederik van de Beek
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Meningitis
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1675-1

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