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Inflammasome activation mediates inflammation and outcome in humans and mice with pneumococcal meningitis

Authors
  • Geldhoff, Madelijn1
  • Mook-Kanamori, Barry B1
  • Brouwer, Matthijs C1
  • Troost, Dirk2
  • Leemans, Jaklien C2
  • Flavell, Richard A3
  • Van der Ende, Arie4, 5
  • Van der Poll, Tom6, 7
  • Van de Beek, Diederik1
  • 1 University of Amsterdam, Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 2 University of Amsterdam, Department of Neuropathology, Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 3 Yale University and Howard Hughes Medical Institute, Department of Immunobiology, New Haven, CT, USA , New Haven (United States)
  • 4 University of Amsterdam, Department of Medical Microbiology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 5 University of Amsterdam, The Netherlands Reference Laboratory for Bacterial Meningitis, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 6 University of Amsterdam, Center for Experimental and Molecular Medicine (CEMM), Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, The Netherlands , Amsterdam (Netherlands)
  • 7 University of Amsterdam, Division of Infectious Diseases, Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam, Amsterdam, The Netherlands , Amsterdam (Netherlands)
Type
Published Article
Journal
BMC Infectious Diseases
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jul 31, 2013
Volume
13
Issue
1
Identifiers
DOI: 10.1186/1471-2334-13-358
Source
Springer Nature
Keywords
License
Yellow

Abstract

BackgroundInflammasomes are multi-protein intracellular signaling complexes that have recently been hypothesized to play a role in the regulation of the inflammation response. We studied associations between inflammasome-associated cytokines IL-1β and IL-18 in cerebrospinal fluid (CSF) of patients with bacterial meningitis and clinical outcome, and pneumococcal serotype. In a murine model of pneumococcal meningitis we examined the pathophysiological roles of two inflammasome proteins, NLRP3 (Nod-like receptor protein-3) and adaptor protein ASC (apoptosis-associated speck-like protein).MethodsIn a nationwide prospective cohort study, CSF cytokine levels were measured and related to clinical outcome and pneumococcal serotype. In a murine model of pneumococcal meningitis using Streptococcus pneumoniae serotype 3, we examined bacterial titers, cytokine profiles and brain histology at 6 and 30 hours after inoculation in wild-type (WT), Asc and Nlrp3 deficient mice.ResultsIn patients with bacterial meningitis, CSF levels of inflammasome associated cytokines IL-1β and IL-18 were related to complications, and unfavorable disease outcome. CSF levels of IL-1β were associated with pneumococcal serotype (p<0.001). In our animal model, Asc and Nlrp3 deficient mice had decreased systemic inflammatory responses and bacterial outgrowth as compared to WT mice. Differences between Asc−/− and WT mice appeared sooner after bacterial inoculation and were more widespread (lower pro-inflammatory cytokine levels in both blood and brain homogenate) than in Nlrp3-/-mice. Nlrp3 deficiency was associated with an increase of cerebral neutrophil infiltration and cerebral hemorrhages when compared to WT controls.ConclusionsOur results implicate an important role for inflammasome proteins NLRP3 and ASC in the regulation of the systemic inflammatory response and the development of cerebral damage during pneumococcal meningitis, which may dependent on the pneumococcal serotype.

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