title: Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis.
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.
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-10111 Lausanne, Switzerland;
authors.forename: Athina
authors.initials: A
authors.lastname: Savva
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-10111 Lausanne, Switzerland;
authors.forename: Thierry
authors.identifier: http://orcid.org/0000-0002-9358-0109
authors.initials: T
authors.lastname: Roger
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Valls Serón
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-10111 Lausanne, Switzerland;
authors.forename: Didier
authors.initials: D
authors.lastname: Le Roy
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.affiliation: Department of Medical Microbiology, the Netherlands Reference Laboratory for Bacterial Meningitis, CINIMA, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-10111 Lausanne, Switzerland;
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.affiliation: Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-10111 Lausanne, Switzerland; thierry.calandra@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Calandra
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000276:immunology; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D018895:Microsatellite Repeats; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D013296:Streptococcus pneumoniae / Q000472:pathogenicity
chemical_list: D057134:Antibodies, Neutralizing; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: innate immunity; macrophage migration inhibitory factor; meningitis; polymorphism; sepsis