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Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis

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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.

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Acknowledgments

We thank Barbara Angele and Judith Houben for technical support, and all Dutch physicians participating in the MeninGene study. This study has been funded by grants from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2011 to MB), European Federation of Neurological Sciences (EFNS Scientific Fellowship 2011 to MB), Netherlands Organization for Health Research and Development (ZonMw; NWO-Veni Grant 2012 [916.13.078] to MB; NWO-Veni Grant 2006 [916.76.023], NWO-Vidi Grant [016.116.358] to DB), the Academic Medical Centre (AMC Fellowship 2008 to DB), and the European Research Council (ERC Starting Grant 2011 to DB).

Conflict of interest

The authors report no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), University of Amsterdam, PO Box 22660, 1100 DD, Amsterdam, The Netherlands

    Matthijs C. Brouwer & Diederik van de Beek

  2. Department of Experimental Vascular Medicine, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands

    Joost C. M. Meijers

  3. Department of Genome Analysis, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands

    Frank Baas

  4. Department of Medical Microbiology, Academic Medical Center, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, The Netherlands

    Arie van der Ende

  5. The Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam, The Netherlands

    Arie van der Ende

  6. Laboratory of Neuroinfectious Diseases, Department of Neurology, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany

    Matthijs C. Brouwer, Hans-Walter Pfister & Uwe Koedel

  7. Center for Neuropathology, Ludwig Maximilians University, Munich, Germany

    Armin Giese

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  1. Matthijs C. Brouwer
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Correspondence to Matthijs C. Brouwer.

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D. van de Beek and U. Koedel contributed equally.

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Brouwer, M.C., Meijers, J.C.M., Baas, F. et al. Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis. Acta Neuropathol 127, 553–564 (2014). https://doi.org/10.1007/s00401-013-1216-4

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