Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis.

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Version: Author's accepted manuscript
Serval ID
serval:BIB_5662A8140129
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Savva A., Brouwer M.C., Roger T., Valls Serón M., Le Roy D., Ferwerda B., van der Ende A., Bochud P.Y., van de Beek D., Calandra T.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
113
Number
13
Pages
3597-3602
Language
english
Abstract
Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.
Keywords
Adult, Aged, Animals, Antibodies, Neutralizing/administration & dosage, Case-Control Studies, Cell Line, Disease Models, Animal, Female, Genetic Predisposition to Disease, Humans, Intramolecular Oxidoreductases/antagonists & inhibitors, Intramolecular Oxidoreductases/cerebrospinal fluid, Macrophage Migration-Inhibitory Factors/antagonists & inhibitors, Macrophage Migration-Inhibitory Factors/cerebrospinal fluid, Male, Meningitis, Pneumococcal/cerebrospinal fluid, Meningitis, Pneumococcal/genetics, Mice, Mice, Inbred BALB C, Microsatellite Repeats, Middle Aged, Netherlands/epidemiology, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Prospective Studies, Streptococcus pneumoniae/pathogenicity
Pubmed
Web of science
Open Access
Yes
Create date
17/03/2016 18:45
Last modification date
20/08/2019 15:10
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