Research output: Contribution to journal › Article › Academic › peer-review
Complement factor H contributes to mortality in humans and mice with bacterial meningitis. / Kasanmoentalib, E. Soemirien; Valls Serón, Mercedes; Engelen-Lee, Joo Yeon et al.
In: Journal of neuroinflammation, Vol. 16, No. 1, 279, 2019.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Complement factor H contributes to mortality in humans and mice with bacterial meningitis
AU - Kasanmoentalib, E. Soemirien
AU - Valls Serón, Mercedes
AU - Engelen-Lee, Joo Yeon
AU - Tanck, Michael W.
AU - Pouw, Richard B.
AU - van Mierlo, Gerard
AU - Wouters, Diana
AU - Pickering, Matthew C.
AU - van der Ende, Arie
AU - Kuijpers, Taco W.
AU - Brouwer, Matthijs C.
AU - van de Beek, Diederik
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85077322257&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31883521
U2 - 10.1186/s12974-019-1675-1
DO - 10.1186/s12974-019-1675-1
M3 - Article
C2 - 31883521
VL - 16
JO - Journal of neuroinflammation
JF - Journal of neuroinflammation
SN - 1742-2094
IS - 1
M1 - 279
ER -
ID: 10515517