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

Geldhoff M, Mook-Kanamori BB, Brouwer MC, Troost D, Leemans JC, Flavell RA, Van der Ende A, Van der Poll T, Van de Beek D - BMC Infect. Dis. (2013)

Bottom Line: 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.Our 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

Background: Inflammasomes 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).

Methods: In 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.

Results: In 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.

Conclusions: Our 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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Bacterial outgrowth in blood, spleen, lung brain and CSF. Bacterial titers in WT vs., Nlrp3−/− mice at 6 (A) and 30 hours (B); and WT vs. and Asc−/− mice at 6 (C) and 30 hours (D) after induction of pneumococcal meningitis. Twelve mice per group were analyzed. Data are given as medians and 75th quartile. * P < 0.05.
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Figure 3: Bacterial outgrowth in blood, spleen, lung brain and CSF. Bacterial titers in WT vs., Nlrp3−/− mice at 6 (A) and 30 hours (B); and WT vs. and Asc−/− mice at 6 (C) and 30 hours (D) after induction of pneumococcal meningitis. Twelve mice per group were analyzed. Data are given as medians and 75th quartile. * P < 0.05.

Mentions: Nlrp3−/− mice showed more bacterial outgrowth in CSF at 6 h compared to WT mice (median 9.2 x 105 CFU/ml versus 2.2 x 105 CFU/ml, p=0.046 Figure 3A). However, Nlrp3−/− had less bacterial outgrowth in blood and spleen at 30 h, as compared to WT mice (blood, 5.7 × 103 CFU/ml versus 3.2 × 104 CFU/ml, p=0.017; spleen, 8.0 × 103 CFU/ml versus 4.7 × 105 CFU/ml, p=0.012 Figure 3B). No differences in bacterial outgrowth in brain homogenates were observed. Asc−/− mice showed less bacterial outgrowth at 6 h in blood and lung compared to WT mice (blood, 2.0 × 103 CFU/ml versus 6.6 × 103 CFU/ml, p=0.017; lung, 2.0 × 103 CFU/ml versus 1.1 × 105 CFU/ml, p=0.043 Figure 3C). At 30 h Asc−/− mice showed less bacterial outgrowth in blood (3.9 x 104 CFU/ml versus 1.4 × 105 CFU/ml, p=0.039 Figure 3D) and spleen (3.1 × 104 CFU/ml versus 6.7 × 104 CFU/ml, p=0.016). No differences in bacterial outgrowth in CSF or brain homogenates in Asc−/− mice were observed.


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

Geldhoff M, Mook-Kanamori BB, Brouwer MC, Troost D, Leemans JC, Flavell RA, Van der Ende A, Van der Poll T, Van de Beek D - BMC Infect. Dis. (2013)

Bacterial outgrowth in blood, spleen, lung brain and CSF. Bacterial titers in WT vs., Nlrp3−/− mice at 6 (A) and 30 hours (B); and WT vs. and Asc−/− mice at 6 (C) and 30 hours (D) after induction of pneumococcal meningitis. Twelve mice per group were analyzed. Data are given as medians and 75th quartile. * P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750264&req=5

Figure 3: Bacterial outgrowth in blood, spleen, lung brain and CSF. Bacterial titers in WT vs., Nlrp3−/− mice at 6 (A) and 30 hours (B); and WT vs. and Asc−/− mice at 6 (C) and 30 hours (D) after induction of pneumococcal meningitis. Twelve mice per group were analyzed. Data are given as medians and 75th quartile. * P < 0.05.
Mentions: Nlrp3−/− mice showed more bacterial outgrowth in CSF at 6 h compared to WT mice (median 9.2 x 105 CFU/ml versus 2.2 x 105 CFU/ml, p=0.046 Figure 3A). However, Nlrp3−/− had less bacterial outgrowth in blood and spleen at 30 h, as compared to WT mice (blood, 5.7 × 103 CFU/ml versus 3.2 × 104 CFU/ml, p=0.017; spleen, 8.0 × 103 CFU/ml versus 4.7 × 105 CFU/ml, p=0.012 Figure 3B). No differences in bacterial outgrowth in brain homogenates were observed. Asc−/− mice showed less bacterial outgrowth at 6 h in blood and lung compared to WT mice (blood, 2.0 × 103 CFU/ml versus 6.6 × 103 CFU/ml, p=0.017; lung, 2.0 × 103 CFU/ml versus 1.1 × 105 CFU/ml, p=0.043 Figure 3C). At 30 h Asc−/− mice showed less bacterial outgrowth in blood (3.9 x 104 CFU/ml versus 1.4 × 105 CFU/ml, p=0.039 Figure 3D) and spleen (3.1 × 104 CFU/ml versus 6.7 × 104 CFU/ml, p=0.016). No differences in bacterial outgrowth in CSF or brain homogenates in Asc−/− mice were observed.

Bottom Line: 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.Our 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Center of Infection and Immunity Amsterdam-CINIMA, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT

Background: Inflammasomes 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).

Methods: In 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.

Results: In 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.

Conclusions: Our 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.

Show MeSH
Related in: MedlinePlus