Complement factor H contributes to mortality in humans and mice with bacterial meningitis.
Animal models
Anti-inflammatory therapy
Bacterial meningitis
Complement factor H
Complement system
Pneumococcal meningitis
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
28 Dec 2019
28 Dec 2019
Historique:
received:
02
09
2019
accepted:
16
12
2019
entrez:
30
12
2019
pubmed:
31
12
2019
medline:
15
7
2020
Statut:
epublish
Résumé
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. 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 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 Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSION
CONCLUSIONS
Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.
Identifiants
pubmed: 31883521
doi: 10.1186/s12974-019-1675-1
pii: 10.1186/s12974-019-1675-1
pmc: PMC6935240
doi:
Substances chimiques
Complement Factor H
80295-65-4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
279Subventions
Organisme : European Union, EUCLIDS
ID : EC-GA no. 279185
Organisme : ZonMw
ID : 016.116.358
Pays : Netherlands
Organisme : ZonMw
ID : 916.13.078 and 917.17.308
Pays : Netherlands
Organisme : Wellcome Trust
ID : 212252/Z/18/Z
Pays : United Kingdom
Organisme : H2020 European Research Council
ID : 281156
Références
PLoS One. 2016 Feb 12;11(2):e0149307
pubmed: 26872035
N Engl J Med. 2002 Nov 14;347(20):1549-56
pubmed: 12432041
Lancet. 2012 Nov 10;380(9854):1703-11
pubmed: 23141619
Hum Mol Genet. 2013 Dec 1;22(23):4857-69
pubmed: 23873044
Brain. 2019 Nov 1;142(11):3325-3337
pubmed: 31373605
J Immunol. 2012 Jan 1;188(1):426-35
pubmed: 22140259
BMC Infect Dis. 2012 Mar 28;12:71
pubmed: 22455545
J Neuroinflammation. 2015 Aug 15;12:149
pubmed: 26272468
Lancet. 2012 Nov 10;380(9854):1693-702
pubmed: 23141618
Lancet Infect Dis. 2018 Apr;18(4):441-451
pubmed: 29395999
Lancet. 2012 Nov 10;380(9854):1623-4
pubmed: 23141602
Sci Rep. 2016 Nov 02;6:35842
pubmed: 27805046
PLoS One. 2016 Mar 23;11(3):e0152164
pubmed: 27007437
Clin Exp Immunol. 2008 Feb;151(2):210-30
pubmed: 18190458
Lancet Neurol. 2010 Mar;9(3):254-63
pubmed: 20138011
Lancet Infect Dis. 2016 Mar;16(3):339-47
pubmed: 26652862
J Immunol. 2007 Feb 1;178(3):1861-9
pubmed: 17237437
BMC Infect Dis. 2015 Feb 14;15:61
pubmed: 25885764
J Infect Dis. 2016 Jun 1;213(11):1820-7
pubmed: 26802141
Cochrane Database Syst Rev. 2015 Sep 12;(9):CD004405
pubmed: 26362566
J Neuroinflammation. 2017 Jan 3;14(1):2
pubmed: 28086930
J Infect. 2014 Jun;68(6):542-7
pubmed: 24412248
J Cell Mol Med. 2008 Aug;12(4):1074-84
pubmed: 18419792
Blood. 2003 Nov 15;102(10):3702-10
pubmed: 12881318
Cell Mol Life Sci. 2017 May;74(9):1605-1624
pubmed: 27942748
Clin Exp Immunol. 1996 Sep;105(3):511-6
pubmed: 8809142
PLoS One. 2015 Mar 23;10(3):e0120757
pubmed: 25798599
J Immunol. 2008 Nov 15;181(10):7138-46
pubmed: 18981135
J Immunol. 2002 Feb 15;168(4):1886-94
pubmed: 11823523
Nat Rev Dis Primers. 2016 Nov 03;2:16074
pubmed: 27808261
Acta Neuropathol Commun. 2016 Mar 22;4:26
pubmed: 27001057
N Engl J Med. 2004 Oct 28;351(18):1849-59
pubmed: 15509818
Clin Exp Immunol. 2008 Jan;151(1):1-13
pubmed: 18081690
N Engl J Med. 2006 Jan 5;354(1):44-53
pubmed: 16394301
Am J Pathol. 2015 Jan;185(1):29-42
pubmed: 25447048
Nat Genet. 2002 Aug;31(4):424-8
pubmed: 12091909
Infect Immun. 1984 Oct;46(1):81-6
pubmed: 6480117
J Immunol. 2009 Apr 1;182(7):4368-77
pubmed: 19299737
Nat Genet. 2010 Sep;42(9):772-6
pubmed: 20694013
Kidney Int. 2010 Aug;78(3):279-86
pubmed: 20445496
Clin Microbiol Rev. 2011 Jul;24(3):557-91
pubmed: 21734248
PLoS Genet. 2011 May;7(5):e1002079
pubmed: 21637784
PLoS One. 2013 Jul 19;8(7):e69783
pubmed: 23894538
FEMS Microbiol Lett. 2006 Nov;264(1):98-103
pubmed: 17020554
J Infect Dis. 2005 Dec 1;192(11):1996-2003
pubmed: 16267773
J Infect Dis. 2002 Dec 1;186 Suppl 2:S225-33
pubmed: 12424702
Clin Exp Immunol. 2004 Dec;138(3):439-46
pubmed: 15544620
J Neurol Neurosurg Psychiatry. 2007 Oct;78(10):1092-6
pubmed: 17353256
Scand J Infect Dis. 2006;38(9):764-71
pubmed: 16938729
Curr Opin Neurol. 2010 Jun;23(3):312-8
pubmed: 20442574
Nephrology (Carlton). 2018 Dec;23(12):1096-1106
pubmed: 29240274
Lancet Neurol. 2008 Jul;7(7):637-48
pubmed: 18565457
Lancet. 1976 May 15;1(7968):1031-4
pubmed: 57446
J Clin Invest. 2011 Oct;121(10):3943-53
pubmed: 21926466
Infect Immun. 1999 Sep;67(9):4517-24
pubmed: 10456894