John J. Roord

IL-1 Receptor Type 1 Gene-Deficient Mice Demonstrate an Impaired Host Defense Against Pneumococcal Meningitis

The fatality rate associated with Streptococcus pneumoniae meningitis remains high despite adequate antibiotic treatment. IL-1 is an important proinflammatory cytokine, which is up-regulated in brain tissue after the induction of meningitis. To determine the role of IL-1 in pneumococcal meningitis we induced meningitis by intranasal inoculation with 8 × 104 CFU of S. pneumoniae and 180 U of hyaluronidase in IL-1R type I gene-deficient (IL-1R−/−) mice and wild-type mice. Meningitis resulted in elevated IL-1α and IL-1β mRNA and protein levels in the brain. The absence of an intact IL-1 signal was associated with a higher susceptibility to develop meningitis. Furthermore, the lack of IL-1 impaired bacterial clearance, as reflected by an increased number of CFU in cerebrospinal fluid of IL-1R−/− mice. The characteristic pleocytosis of meningitis was not significantly altered in IL-1R−/− mice, but meningitis was associated with lower brain levels of cytokines. The mortality was significantly higher and earlier in the course of the disease in IL-1R−/− mice. These results demonstrate that endogenous IL-1 is required for an adequate host defense in pneumococcal meningitis.

Experimental Pneumococcal Meningitis in Mice: A Model of Intranasal Infection

Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In this study, a novel model of murine meningitis is described. Intranasal administration of S. pneumoniae with hyaluronidase induced meningitis in 50% of inoculated mice, as defined by a positive cerebrospinal fluid (CSF) culture and an inflammatory infiltrate in the meninges. None of the mice inoculated without hyaluronidase developed meningitis. Hyaluronidase was found to facilitate pneumococcal invasion of the bloodstream after colonization of the upper respiratory tract. Meningitis was characterized by pleocytosis of CSF and the induction of proinflammatory cytokines and CXC chemokines in brain tissue. These results indicate that this murine model mimics important features of human disease and allow for the use of this model for studying issues related to the pathophysiology and the treatment of pneumococcal meningitis.

Interleukin-18 gene-deficient mice show enhanced defense and reduced inflammation during pneumococcal meningitis.

To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of both pro- and mature IL-18 in brain tissue in WT mice. IL-18(-/-) and WT mice were equally susceptible to develop meningitis after intranasal infection, yet IL-18(-/-) mice showed a prolonged survival and a suppressed inflammatory response, as reflected by a less profound inflammatory infiltrate around the meninges and lower concentrations of cytokines and chemokines in brain tissue. These findings suggest that endogenous IL-18 contributes to a detrimental inflammatory response during pneumococcal meningitis and that elimination of IL-18 may improve the outcome of this disease.

CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats.

Intracisternal injection of the CXC-chemokines KC or macrophage inflammatory protein (MIP)-2 induced a pleocytosis in the cerebrospinal fluid (CSF) of rats in a dose dependent way. MIP-2 was much more potent than KC. The concurrent injection of both chemokines revealed a profound synergistic effect on leukocyte recruitment into CSF.

Interleukin-10 negatively regulates local cytokine and chemokine production but does not influence antibacterial host defense during murine pneumococcal meningitis.

ABSTRACT To determine the role of endogenous interleukin-10 (IL-10) in local host defense during pneumococcal meningitis, the inflammatory responses of IL-10-gene-deficient and wild-type mice after the induction of meningitis were compared. The absence of IL-10 was associated with higher cytokine and chemokine concentrations and a more pronounced infiltrate, but antibacterial defense or survival was not influenced.

Chemotactic Factors in Cerebrospinal Fluid during Bacterial Meningitis

Bacterial meningitis is a devastating infectious disease, with a worldwide mortality rate of 20 to 30% despite antibiotic treatment (43, 45, 58). As many as 50% of survivors encounter neurological sequelae, such as hearing impairment, seizure disorders, and learning and behavioral problems (22, 32, 65). n nIn general, bacterial meningitis develops either when bacteria enter the systemic circulation and subsequently invade the central nervous system (CNS) or via continuous spread during a focal infection in the vicinity of the CNS (30, 57). The multiplication of bacteria in the CNS triggers a localized immune response, characterized by an influx of leukocytes. In a healthy state, the CNS is devoid of identifiable leukocytes (24, 91). However, in pathological conditions, leukocytes enter the brain in response to a variety of stimuli. Bacterial meningitis is characterized by pleocytosis of the cerebrospinal fluid (CSF), consisting predominantly of polymorphonuclear leukocytes (PMNs). n nLeukocyte recruitment is a key aspect of the protective response against invading microorganisms, but over recent years, evidence has accumulated that leukocytes also contribute importantly to tissue damage in bacterial meningitis (30, 43, 46, 65, 85). Although leukocytes within the CSF are important for host defense, it has been demonstrated repeatedly that inhibition of leukocyte recruitment does not necessarily reduce bacterial clearance in the CNS (15, 51, 82). Altogether, leukocyte accumulation in CSF seems a useful target for additional therapeutic strategies. n nChemotaxis, directed migration of leukocyte subsets toward the CNS, is a complex process of which we have limited knowledge. First, leukocytes must adhere to endothelial cells, a process in which specific adhesion molecules (selectins) are involved, producing a rolling motion of leukocytes along the endothelium (81). Heparin interferes with this process and attenuates leukocyte rolling and sticking (89). In a secondary phase, mediated by integrins, leukocytes become strongly adherent, and once firmly attached, they can migrate between endothelial cell junctions (diapedesis) along a chemotactic gradient (60, 62, 80). n nIn 1975, Nolan et al. reported that CSF from patients with pneumococcal meningitis is chemotactic for granulocytes in vitro (47), a finding that was later confirmed by others (21, 35, 71, 95). Over recent decades, the chemotactic capacity of CSF of patients with bacterial meningitis has been further analyzed, and experimental models have provided more insight into the role of specific chemotactic factors in leukocyte trafficking during meningitis. In the present review, we summarize the available data on chemotactic factors that contribute to the development of pleocytosis during bacterial meningitis.

Chemotactic activity of CXCL5 in cerebrospinal fluid of children with bacterial meningitis.

CXCL5 (epithelial-cell-derived neutrophil-activating protein (ENA-)78) is a CXC-chemokine that specifically acts on neutrophils. To obtain insight into the extent of local presence and action of CXCL5 during bacterial meningitis, we measured its concentrations in cerebrospinal fluid (CSF) of patients with culture-proven bacterial meningitis (n=14), aseptic meningitis (n=6), and controls (n=32) and compared these results with levels of other CXC-chemokines, CXCL8- (interleukin-8) and CXCL1-related oncogene (growth-related oncogene (GRO)-alpha). Patients with bacterial meningitis had profoundly elevated CSF concentrations of all three chemokines. CXCL5 was not detectable in patients with aseptic meningitis or control subjects. CSF from patients with bacterial meningitis exerted chemotactic activity towards neutrophils, which was partially inhibited by neutralizing antibodies against CXCL5 and CXCL8, but not CXCL1. CSF from controls exerted minor chemotactic activity, which could be strongly enhanced by the addition of recombinant CXCL5, CXCL8 or CXCL1. During bacterial meningitis, CXCL5 is elevated in CSF, where it is involved in the recruitment of neutrophils to the central nervous system.

Academic and behavioral limitations and health-related quality of life in school-age survivors of bacterial meningitis

The objectives of this study were to describe health-related quality of life of postmeningitic children and to examine the association between academic and/or behavioral limitations and health-related quality of life. One hundred and eighty-two children (mean age 9.7xa0years; range 5.3–14.2) were selected randomly from a cohort of 674 school-age children who recovered from non-Haemophilus influenzae type B bacterial meningitis. These children had neither meningitis with ‘complex onset’, nor prior cognitive or behavioral problems, nor severe disease sequelae. On average 7.4xa0years after meningitis, they were evaluated using an ‘Academic Achievement Test’ and their parents filled in the Child Behavior Checklist, the Child Health Questionnaire, and the Health Utilities Index. The long-term incidence of academic and/or behavioral limitations was 32%. Overall health-related quality of life of the postmeningitic children was decreased in comparison with that of a reference population of schoolchildren. The group of postmeningitic children with academic and/or behavioral limitations showed the most marked decrease in quality of life, especially concerning psychosocial health, cognition and family life. The negative effects on quality of life were not significantly influenced by age, gender, causative pathogen, presence of minor neurological impairment, or presence of hearing impairment. In conclusion, health-related quality of life of postmeningitic children is decreased, particularly of those with academic and/or behavioral limitations.

C1 Inhibitor Treatment Improves Host Defense in Pneumococcal Meningitis in Rats and Mice

In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement inhibition by C1 inhibitor (C1-inh) is beneficial in animal models of endotoxemia and sepsis. In the present study, we demonstrate classical pathway complement activation during pneumococcal meningitis in rats. We also evaluate the effect of C1-inh treatment on clinical illness, bacterial clearance, and inflammatory responses in rats and mice with pneumococcal meningitis. C1-inh treatment was associated with reduced clinical illness, a less-pronounced inflammatory infiltrate around the meninges, and lower brain levels of proinflammatory cytokines and chemokines. C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis.

Neuropsychology of academic and behavioural limitations in school-age survivors of bacterial meningitis.

Neuropsychological impairments possibly underlying academic and/or behavioural limitations were studied in 149 school‐age survivors of bacterial meningitis, 68 with and 81 without academic and/or behavioural limitations. Academic limitations affected mathematics, reading, and writing. Behavioural limitations were inferred from scores in the clinical range on the Child Behaviour Checklist. These children had been selected from a cohort of 674 children (57% males) who had recovered from non‐Haemophilus influenzae type B bacterial meningitis and who had a mean age at infection of 2 years 4 months (range 1mo to 9y 5mo). They had neither‘complex onset’meningitis, prior cognitive or behavioural problems, nor severe disease sequelae. They were assessed with standardized assessment methods a mean of 7.8 years (range 4 to 10.4) after meningitis. Children with limitations (32% of the cohort) performed generically poorly on measures of cognitive functioning, speed, and motor steadiness, rather than having impairments in specific neuropsychological domains. The presence of two or more minor neurological signs was more frequent in the group with than in the group without limitations (30% versus 9%); this may explain the relatively poor speed and motor steadiness of the group with limitations.