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 CATT 5-8 ; 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 CATT 7 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 CATT 7 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. macrophage migration inhibitory factor | polymorphism | meningitis | sepsis | innate immunity

Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life

“…Yet, no polymorphisms of the DDT gene have been reported. While carriage of high expression MIF alleles was generally associated with more severe complications and poor outcome, it has also been associated with survival in patients with community-acquired pneumonia (17, 65, 66). Our findings of higher MIF levels in infants who did not develop BPD or LOS are consistent with a previous study showing an association between carriage of a high expression MIF allele and a lower incidence of BPD in preterm newborns (30).…”

“…Our findings of higher MIF levels in infants who did not develop BPD or LOS are consistent with a previous study showing an association between carriage of a high expression MIF allele and a lower incidence of BPD in preterm newborns (30). We did not determine the MIF genotype of the very preterm newborns because genetic material was unavailable and because such a study would be strongly underpowered considering MIF allele frequencies and patient number (14, 16, 17). A nationwide pediatric sepsis cohort study has been launched in Switzerland and will address the relationship between MIF and DDT gene polymorphisms and expression levels and clinical outcome (58, 67).…”

“…MIF levels are also increased in the circulation of septic patients and correlate with dysregulated pituitary and adrenal function, inflammatory response, severity scores, and disease outcome (10–13). Functional polymorphisms of the MIF gene affecting MIF expression levels have been associated with susceptibility to or severity of autoimmune, infectious, and oncologic diseases (14–17). Altogether, MIF is considered as a potential biomarker/genetic marker and an attractive target for immunomodulating therapies for a number of diseases (14, 15, 18–24).…”

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

“…Propionate and butyrate were from Sigma-Aldrich, valproate from Desitin (Hamburg, Germany), Salmonella minnesota ultra pure lipopolysaccharide (LPS) from List Biologicals Laboratories (Campbell, CA) and Pam 3 CSK 4 from EMC microcollections (Tübingen, Germany). E. coli O18:K1:H7 ( E. coli ), K. pneumoniae caroli ( K. pneumoniae ), S. aureus AW7 ( S. aureus ), S. pneumoniae 6303 ( S. pneumoniae ), and C. albicans were isolated from septic patients7172. E. coli, K. pneumoniae, S. aureus and S. pneumoniae were grown in brain heart infusion broth, C. albicans in yeast extract-peptone-dextrose (BD Biosciences, Erembodegem, Belgium).…”

Association study of <em>MIF</em> promoter polymorphisms with suicide completers in the Japanese population

“…The MIF gene promoter contains two functional variations: MIF -794CATT 5–8 repeat (rs5844572) and MIF -173G/C single-nucleotide polymorphism (SNP) (rs755622), which have been well documented to affect the gene expression and protein levels of MIF 27,28. Indeed, many studies have examined the association between these two polymorphisms and various physical diseases 29–34. However, no previous study has investigated the role of both these polymorphisms in suicidal behavior.…”