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.

Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis

“…Subsequently, the complement system is activated, leading to massive release of anaphylotoxins and chemotaxis and activation of neutrophils [11]. Genetic variants in complement system, TLR and IL-1R signaling pathways, and the M-TOR pathway have been identified to be associated with outcome in pneumococcal meningitis [7, 9, 12–15]. Inhibition of the final common pathway in the complement cascade has been identified as target for adjunctive treatment for experimental pneumococcal meningitis.…”

HIF-1α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis

“…For intracerebral infection, mice received 10 µl of 10 5 CFU/ml of S. pneumoniae D39 after i.p anesthesia with ketamine (100 mg/kg) and xylazine (10 mg/kg) as described previously [32]. For intracisternal infection, 15 µl of 10 7 CFU/ml of S. pneumoniae D39 strain was injected under brief anesthesia with isofluorane [6]. Animals were sacrificed between 24 and 48 h post-infection and brains were extracted and formalin fixed, followed by embedding in paraffin for use in immunohistochemistry.…”

Role of t-PA and PAI-1 variants in temporal lobe epilepsy in Chinese Han population

“…In addition, another single guanine nucleotide Insertion/Deletion polymorphism (−/G) is located in the promoter region of the PAI-1 gene, which was claimed to influence the expression of PAI-1 [22]. Although previous data showed that these SNPs were not only associated with multiple thrombotic disorders, such as strokes [20, 22, 28], myocardial infarction [29–31], but also with the severity of bacterial infections, such as meningitis [32, 33], it remains blank concerning the relationship between t-PA , PAI-1 polymorphisms and TLE.…”