title: Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis.
abstract: Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwide prospective cohort study we evaluated the effect of the 4G/5G polymorphism (rs1799889) in SERPINE1 (coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03-2.78] and mortality (OR 2.20, 95 % CI 1.02-4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (P = 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (P = 0.015) and haemorrhages (P = 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using Serpine1 knockout mice. Consistent with the human data, Serpine1-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications.
authors.affiliation: Department of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, The Netherlands, m.c.brouwer@amc.uva.nl.
authors.forename: Matthijs C
authors.initials: MC
authors.lastname: Brouwer
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Arie
authors.initials: A
authors.lastname: van der Ende
authors.forename: Hans-Walter
authors.initials: HW
authors.lastname: Pfister
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.forename: Diederik
authors.initials: D
authors.lastname: van de Beek
authors.forename: Uwe
authors.initials: U
authors.lastname: Koedel
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000209:etiology* / Q000401:mortality*; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000150:complications* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D017395:Plasminogen Activator Inhibitor 1