Response In Bacterial Meningitis Research Articles

Cerebrospinal fluid sex steroid hormones in bacterial meningitis.

Unfavorable outcome in bacterial meningitis is related to excessive inflammation and higher inflammatory markers have been reported in female than in male patients. Sex steroid hormones have immunomodulatory properties and can be found in the cerebrospinal fluid (CSF); however, their actions have not been studied in bacterial meningitis. We investigated the association between CSF sex steroid hormone levels and inflammatory parameters, disease severity, and outcome in pneumococcal meningitis. We identified adults with culture-proven pneumococcal meningitis in a prospective cohort study (2006-2014). We measured estradiol and testosterone in CSF using liquid chromatography-tandem mass spectrometry and sex hormone-binding globulin (SHBG) using an enzyme-linked immunoassay. Hormone levels were compared according to outcome, which was graded using the Glasgow Outcome Scale (a score of 5 indicating favorable, 1-4 unfavorable outcome). Correlation analysis was used to measure the association between hormone levels and inflammatory cytokines, chemokines, and complement factors as well as severity of illness, as measured by the Glasgow Coma Scale and the Dutch Meningitis Risk Score. We included 60 patients: 20 men, 20 premenopausal (<50 years), and 20 postmenopausal (>50 years) women. Twenty-one (35%) patients had an unfavorable outcome and 11 (18%) died. Cases with an unfavorable outcome exhibited higher estradiol (median 14.0 vs 5.0 pmol/L, P = .04) and lower SHBG (0.40 vs 1.0 nmol/L, P = .03) levels compared with those with a favorable outcome. Estradiol was positively correlated with C-reactive protein (R = 0.42, P = .001), CSF protein (R = 0.33, P = .01), and proinflammatory cytokine levels. CSF concentrations of the sex steroid hormone estradiol were associated with outcome and CSF inflammation. Understanding the dose and time-dependent interaction between sex steroid hormones and the inflammatory response in bacterial meningitis represents an important and understudied topic.

Protein Oxidation Biomarkers and Myeloperoxidase Activation in Cerebrospinal Fluid in Childhood Bacterial Meningitis.

The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2′-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO₂-Tyr) and 8-oxo-2′-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p < 0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO₂-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.

Immediate Neutrophil-Variable-T Cell Receptor Host Response in Bacterial Meningitis.

Bacterial meningitis is a life-threatening disease that evokes an intense neutrophil-dominated host response to microbes invading the subarachnoid space. Recent evidence indicates the existence of combinatorial V(D)J immune receptors in neutrophils that are based on the T cell receptor (TCR). Here, we investigated expression of the novel neutrophil TCRαβ-based V(D)J receptors in cerebrospinal fluid (CSF) from human patients with acute-phase bacterial meningitis using immunocytochemical, genetic immunoprofiling, cell biological, and mass spectrometric techniques. We find that the human neutrophil combinatorial V(D)J receptors are rapidly induced in CSF neutrophils during the first hours of bacterial meningitis. Immune receptor repertoire diversity is consistently increased in CSF neutrophils relative to circulating neutrophils and phagocytosis of baits directed to the variable immunoreceptor is enhanced in CSF neutrophils during acute-phase meningitis. Our results reveal that a flexible immune response involving neutrophil V(D)J receptors which enhance phagocytosis is immediately initiated at the site of acute bacterial infection.

Transcriptomics of toll like receptor signaling pathway in children with acute bacterial meningitis

Background : The invading bacterial pathogens are recognized by a class of pathogen recognition receptors (PRRs) called Toll Like receptors (TLRs) present on immune cells. PRRs play an important role in elimination of pathogens in early part of the disease but also results in unabated inflammation. There is a sparse literature on TLR transcriptome and their role in mediating immune response in bacterial meningitis. Methods : Children hospitalized with bacterial meningitis (ABM, n=30) and aseptic meningitis (ASM, n=11) were enrolled. Controls (n=15) included the children, where CSF tap didn’t yield any infection on lab investigation. The gene expression profile of forty-two genes of TLR signaling pathway was performed using PCR array platform. Further, these results were validated by estimating secretory cytokines and chemokines in CSF using Luminex platform and western blotting. Results : We observed an increased expression of TLR2 (2 folds),TLR3 (13 folds), TLR8 (3 folds), TLR9 (20 folds), CD180(8 folds), TICAM1 and TIRAP dependent signaling pathway genes including of TNF? (8 folds), IL6 (114 folds), IL12 (64 folds), IL10 (17 folds), CCL4 (18 folds), CCL5 (7 folds) and CXCL8 (31 folds) in children with ABM. The protein expression of TLR signaling genes (TLR3,TNF?,IL-1ÃY, IL-6,IL-8, IL10,IL1ra) was observed to increase in children with ABM in comparison with ASM and controls. Further, we also observed higher CSF levels of IL-1ÃY, IL-6, IL-17, IL1ra, IL-8, MCP-1 & RANTES in children with ABM as compared to ASM and controls. Conclusion : An overall upregulation of TLRs and downstream TLR signaling molecules was observed. This subsequently resulted in increased levels of inflammatory cytokines and chemokines in children with ABM. The study provides an insight to role of TLR signaling in augmentation of immune response in pediatric bacterial meningitis which can be further explored for therapeutic intervention to regulate unabated inflammatory process in bacterial meningitis.

Genetic polymorphisms associated with the inflammatory response in bacterial meningitis.

BackgroundBacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously.MethodsThe study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method.ResultsWe did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients.ConclusionsIn conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0218-6) contains supplementary material, which is available to authorized users.

Immunopathogenetic features of bacterial purulent meningitides

The aim of the study. Comparative assessment of the state of cells of the immune system in patients with purulent bacterial meningitides caused by N.meningitidis and S.pneumoniae . Materials and methods. By the method offlow cytofluorometry there were tested blood and cerebrospinal fluid of 65 patients with bacterial purulent meningitis, with the meningococcal (38 people) and pneumococcal (27 people) nature of the disease. Results. There were revealed general consistencies of the immune response to CNS infection with meningococcus andpneumococcus: the fall of the number of CD16+ CD56+(NK) and the gain in the number of CD19+ cells in the blood, an increase in the absolute number of T lymphocytes, especially, CD3+ CD8+ and NK. In pneumococcal meningitis there was noted the more pronounced upsurge in the absolute number of the NKT (CD3+CD56+) and B-lymphocytes in the blood whereas in cerebrospinal fluid - the more pronounced upturn in the absolute number of NKT that testified to the severe course of the disease. Conclusion. As a result of performed studies there was identified a series of consistencies for the development of the immune response in bacterial purulent meningitides of meningococcal and pneumococcal etiology, which show the high informativeness of the study of immunograms of cerebrospinal fluid in these diseases as compared with blood. In the latter case, immunological studies may contribute not only to the identification of general consistencies of the development of the immune response in bacterial meningitis, but also serve as a basis for the differentiation of the impact of meningococcal and pneumococcal infection on immunocompetent cells, as well as to reflect the severity of the course of the disease, affecting the nature of the therapy.

Predictive Value of Cerebrospinal Fluid Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Concentrations in Childhood Bacterial Meningitis

Increased concentrations of matrix metalloproteinases (MMP) in cerebrospinal fluid are part of the host response in bacterial meningitis (BM). We investigated whether the concentrations of MMP-9 and the tissue inhibitor of metalloproteinase (TIMP)-1 predict the outcome in childhood BM. Cerebrospinal fluid MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were quantified by an enzyme-linked immunosorbent assay from 264 and 335 patients, respectively; 43 children without BM served as controls. The results were compared with previously known independent predictors of death and sequelae. Higher MMP-9 and TIMP-1 values distinguished the controls from the BM patients (P < 0.0001). A MMP-9 concentration >940 ng/mL proved an independent predictor of death [adjusted odds ratio: 4.03; 95% confidence interval (CI): 2.09-7.77; P < 0.0001]. If the patient additionally presented with a Glasgow Coma Score below 9, the odds increased to 13.21 (95% CI: 5.44-32.08; P < 0.0001). TIMP-1 levels correlated with the severity of sequelae (ρ: 0.30; P < 0.0001), but not with death. Its concentration above 390 ng/mL increased the likelihood of sequelae 3.43-fold (95% CI: 1·73-6·79; P = 0.0004), and up to 31.18-fold (95% CI: 4.05-239.8; P = 0.0009) if the patient also presented a Glasgow Coma Score < 12. Elevated cerebrospinal fluid MMP-9 and TIMP-1 values predict 2 important outcomes in childhood BM. Combined with a clinical evaluation, quantification of these indices augments the chances to identify the patients in greatest need of better treatment modalities.

Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis

BackgroundThe kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM.MethodsOne hundred and one individuals were enrolled in this study to investigate SNPs in the following genes: indoleamine-2,3-dioxygenase (IDO1 gene), kynureninase (KYNU gene), kynurenine aminotransferase I (CCBL1 gene), and kynurenine aminotransferase II (AADAT gene). SNP analyses were performed by primer-introduced restriction analysis-PCR (PIRA-PCR) followed by RFLP. Cytokines were measured using multiplex bead assay while immunoglobulins (IG) by immunodiffusion plates and NF-kappaB and c-Jun by dot blot assay.ResultsThe variant allele of SNP AADAT+401C/T showed prevalent frequency in patients with BM. A significant decrease (p < 0.05) in TNF-α, IL-1β, IL-6, MIP-1αCCL3 and MIP-1β/CCL4 levels was observed in BM patients homozygous (TT) to the SNP AADAT+401C/T. Furthermore, a significant (p < 0.05) decrease in cell count was observed in cerebrospinal fluid (CSF) from patients with TT genotype. In addition, an increase in the IgG level in adults (p < 0.05) was observed. The variant allele for KYNU+715G/A was found with low frequency in the groups, and the SNPs in IDO1+434T/G, KYNU+693G/A, CCBL1+164T/C, and AADAT+650C/T had no frequency in this population.ConclusionsThis study is the first report of an association of SNP AADAT+401C/T with the host immune response to BM, suggesting that this SNP may affect the host ability in recruitment of leukocytes to the infection site. This finding may contribute to identifying potential targets for pharmacological intervention as adjuvant therapy for BM.

Regulation of activin A synthesis in microglial cells: Pathophysiological implications for bacterial meningitis

Previous studies have shown that activin A, a neuroprotective cytokine and dimeric polypeptide composed of two betaA subunits, is elevated in the cerebrospinal fluid of patients suffering from bacterial meningitis. In this study, to elucidate further the functional significance and pathophysiological implications of these findings, we demonstrated that microglial cells are not only the source but also the target cells of activin A in the central nervous system: immunohistochemistry and RT-PCR revealed expression of activin subunit betaA mRNA as well as activin receptor type I and type II mRNA in rat microglia in vitro. Further studies showed that activin enhances microglial proliferation and decreases the gamma-interferon-induced synthesis of nitric oxide, one of several microglial mediators involved in the inflammatory response in microglia activation. Furthermore, quantitative RT-PCR, Western blotting, and ELISA showed an inhibitory effect of activin on inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta gene and protein levels after lipopolysaccharide treatment. We suggest that the increased synthesis of activin A is directly involved, via influence on microglia cell functions, in the modulation of the inflammatory response in bacterial meningitis.

Mediators of cellular stress response in bacterial meningitis*

Luton & Dunstable Hospital, NHS Foundation Trust, Bedfordshire, UK The author has not disclosed any potential conflicts of interest.

Reprogramming the host response in bacterial meningitis: how best to improve outcome?

Despite effective antibiotic therapy, bacterial meningitis is still associated with high morbidity and mortality in both children and adults. Animal studies have shown that the host inflammatory response induced by bacterial products in the subarachnoid space is associated with central nervous system injury. Thus, attenuation of inflammation early in the disease process might improve the outcome. The feasibility of such an approach is demonstrated by the reduction in neurologic sequelae achieved with adjuvant dexamethasone therapy. Increased understanding of the pathways of inflammation and neuronal damage has suggested rational new targets to modulate the host response in bacterial meningitis, but prediction of which agents would be optimal has been difficult. This review compares the future promise of benefit from the use of diverse adjuvant agents. It appears unlikely that inhibition of a single proinflammatory mediator will prove useful in clinical practice, but several avenues to reprogram a wider array of mediators simultaneously are encouraging. Particularly promising are efforts to adjust combinations of cytokines, to inhibit neuronal apoptosis and to enhance brain repair.

Triptans reduce the inflammatory response in bacterial meningitis.

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.

Effects of polysaccharide fucoidin on cerebrospinal fluid interleukin-1 and tumor necrosis factor alpha in pneumococcal meningitis in the rabbit.

The inflammatory response in bacterial meningitis is mediated by cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1), which are produced in the subarachnoid space by different cells, e.g., leukocytes, astrocytes, and microglia. The recruitment of leukocytes into the cerebrospinal fluid (CSF) has been shown to contribute to the neurological damage in this disease, a process which could be enhanced by treatment with antibiotics. In this study, we have used a rabbit meningitis model for two sets of experiments with intracisternal (i.c.) injections of Streptococcus pneumoniae. First, pneumococcal cell wall (PCW) components were injected i.c., inducing an inflammatory response with pleocytosis and increased levels of CSF TNF-alpha) and IL-1 at 6 and 12 h after PCW injection. Treatment with fucoidin, known to inhibit leukocyte rolling, abolished pleocytosis and inhibited the release of TNF-alpha and IL-1. In the second experiment, live pneumococcal bacteria were injected i.c. and treatment with one dose of ampicillin (40 mg/kg of body weight intravenously) was given 16 h after induction of meningitis, causing a sevenfold increase in CSF leukocytes over a 4-h period. CSF IL-1 levels at 16 h were high but did not increase further at 20 h. Also, CSF TNF-alpha levels were high at 16 h and tended to increase at 20 h. Fucoidin treatment prevented the antibiotic-induced increase of CSF leukocytes but had no effect on the TNF-alpha and IL-1 levels. Taken together, fucoidin reduced CSF TNF-alpha and IL-1 levels in acute bacterial meningitis induced by PCW fragments but had no effect later in the course of the disease, when live bacteria were used and an inflammatory increase was caused by a dose of antibiotics.

Inflammatory response in bacterial meningitis: cytokine levels in the cerebrospinal fluid.

Inflammatory response plays an important role in the pathogenesis of cerebral injury in bacterial meningitis. In this study, we evaluated the cytokine levels of interleukin 1-beta (IL1 beta), tumour necrosis factor alpha (TNF alpha) and interleukin 6 (IL6) in the cerebrospinal fluid (CSF), and determined their correlation with acute clinical complications and with changes in CSF biochemistry. Interleukin 6, TNF alpha and IL1 beta were present in 9/9, 3/9 and 4/9 patients, respectively. The CSFs with detectable TNF alpha or IL1 beta had higher levels of IL6 (p < 0.02), protein (NS) and lower glucose levels (p < 0.02), compared with those in which TNF alpha and IL1 beta were absent. Tumour necrosis factor alpha and IL1 beta levels also correlated with the presence of prolonged fever, fits, spasticity and death (logTNF alpha: r = 0.70, p < 0.05; logIL1 beta: r = 0.62, p = 0.08). The cytokine levels reflect the degree of inflammatory response and are positively correlated with the severity of acute clinical complications. Modulation of this inflammatory response in bacterial meningitis may improve its morbidity and mortality.

γδ T lymphocytes and proinflammatory cytokines in bacterial meningitis

Background: Patients with bacterial meningitis have a T-cell defect and impaired cytokine production. Methods: The phenotype and percentage of circulating αβ and γδ T-cell receptor-bearing lymphocytes were determined from patients with bacterial meningitis ( Haemophilis influenzae, Streptococcus pneumoniae, and Neisseria meningitidis), patients with bacterial infection but without meningitis, and healthy control subjects by a monoclonal antibody staining method. The in vitro production of cytokines, interleukins (IL-2, IL-6), Interferon-γ and tumor necrosis factor-α was measured by the bioassay or ELISAs. Results: The percentage of circulating γδ T cells with a CD3 + CD4 + CD8 — phenotype was significantly ( p < 0.001) increased in all patients with bacterial meningitis compared with patients with bacterial infection and healthy control subjects. The CD3 + γδ T cells from patients with meningitis produced highly elevated levels of two proinflammatory cytokines, tumor necrosis factor-α and IL-6. However, Interferon-γ production was enhanced by CD3 + αβ T cells. Conclusion: The increased percentage of circulating T-cell receptor γδ T cells and their in vitro production of tumor necrosis factor-α and IL-6 cytokines may play an important role in the pathogenesis and inflammatory response in bacterial meningitis.

Ependymal cells of the choroid plexus express tumour necrosis factor-alpha.

Tumour necrosis factor-alpha (TNF alpha) is a major proinflammatory cytokine which appears in the cerebrospinal fluid very early after endotoxin challenge, and is likely to be produced locally. Following in vivo and in vitro challenge with endotoxin, we have demonstrated immunocytochemically and by in situ hybridization that pig and guinea-pig choroid plexus ependymal cells can produce TNF alpha. Immuno-electron microscopy shows that this protein is localized within ependymal cells to the cytoplasm and microvilli. We suggest that this TNF alpha may be important in the initiation of the inflammatory response in bacterial meningitis.

Effect of dexamethasone or HWA-138 in combination with antibiotics in experimental Haemophilus influenzae type b infection

Modulation of the host's inflammatory response in bacterial meningitis may be beneficial. In this study, the effects of dexamethasone and HWA-138, an analog of pentoxifylline, on CSF cultures and cochlear inflammation in an infant rat model of Haemophilus influenzae type b were studied. Five-day-old infant rats were inoculated once intraperitoneally with 1 x 10(4) to 10 x 10(4) CFU of H. influenzae type b (strain 1406). Twenty-four hours later, infant rats were treated intraperitoneally with one dose of ampicillin (0.1 mg/g of body weight), cefotaxime (0.05 mg/g), or cefuroxime (0.05 mg/g) alone or in combination with one dose of dexamethasone (0.00015 mg/g) or HWA-138 (0.005 mg/g). Twenty-four hours after treatment with cefuroxime plus dexamethasone, animals had a significantly (P less than or equal to 0.04) greater incidence of bacteremia and meningitis (eight of nine animals) than that in animals of the other treatment groups. Overall, dexamethasone was associated with less inflammation (P less than 0.04) of the cochlear nerve compared with that from antibiotic treatment alone. In this model, when suboptimal antimicrobial therapy is administered, anti-inflammatory agents may be beneficial with respect to reducing cochlear inflammation. However, dexamethasone and cefuroxime lead to a higher rate of positive blood and cerebral spinal fluid cultures than cefuroxime alone.