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

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.

Tumor Necrosis Factor-α, Interleukins-12(p40), 6, and 10 levels in cerebrospinal fluid and outcome prediction in Ossimi sheep with encephalitic listeriosis

“…On the contrary, in sheep with encephalitic listeriosis, IL-1b in CSF had prognostic value [15]. Moreover, CSF levels of IL-1b and IL-18 were related to complications, and unfavorable outcome of pneumococcal meningitis [41].…”

Infectious immunity in the central nervous system and brain function

“…73). Indeed, caspase-1 deficiency or in vivo use of broad caspase inhibitors in experimental models of bacterial meningitis reduces neuronal damage with mitigation of lethargy and improved motor function 74,75 .…”

Pneumolysin

“…In murine models of pneumococcal meningitis, activation of the inflammasome adaptor molecule ASC and sensor NLRP3 is associated with increased pathology and clinical disease score [66]. In meningitis patients, cerebrospinal fluid levels of IL-1β and IL-18 were correlated with complications and unfavorable outcome [67], and persistence of pneumolysin in patients is associated with mortality [68]. Furthermore, pathology was significantly reduced during infection with pneumolysin-deficient bacteria incapable of inflammasome activation [66] or in mice deficient in ASC or NLRP3 [67].…”