interleukin-8 and Pneumococcal-Infections

The expanding knowledge on the systemic influence of the human microbiome suggests that fecal samples are underexploited sources of new beneficial strains for extra-intestinal health. We have recently shown that acetate, a main circulating microbiota-derived molecule, reduces the deleterious effects of pulmonary

Topics: Animals; Clostridiales; Disease Models, Animal; Humans; Influenza, Human; Interleukin-8; Mice; Orthomyxoviridae Infections; Pneumococcal Infections; Salmonella Infections, Animal; Salmonella typhimurium; Streptococcus pneumoniae

Nonencapsulated Streptococcus pneumoniae bacteria are successful colonizers of the human nasopharynx and often possess genes aliB-like ORF 1 and 2 in place of capsule genes. AliB-like ORF 2 binds peptide FPPQSV, found in Prevotella species, resulting in enhanced colonization. How this response is mediated is so far unknown.. Here we show that the peptide increases expression of genes involved in release of host carbohydrates, carbohydrate uptake and carbohydrate metabolism. In particular, the peptide increased expression of 1,5-anhydro-D-fructose reductase, a metabolic enzyme of an alternative starch and glycogen degrading pathway found in many organisms, in both transcriptomic and proteomic data. The peptide enhanced pneumococcal growth giving a competitive advantage to a strain with aliB-like ORF 2, over its mutant lacking the gene. Possession of aliB-like ORF 2 did not affect release of inflammatory cytokine CXCL8 from epithelial cells in culture and the nonencapsulated wild type strain was not able to establish disease or inflammation in an infant rat model of meningitis.. We propose that AliB-like ORF 2 confers an advantage in colonization by enhancing carbohydrate metabolism resulting in a boost in growth. This may explain the widespread presence of aliB-like ORF 2 in the nonencapsulated pneumococcal population in the human nasopharynx.

Topics: Animals; Bacterial Capsules; Bacterial Proteins; Carbohydrate Metabolism; Carrier Proteins; Cell Line; Cytokines; Disease Models, Animal; Epithelial Cells; Gene Expression Regulation, Bacterial; Genes, Bacterial; Glycogen; Humans; Interleukin-8; Lipoproteins; Nasopharynx; Peptides; Pneumococcal Infections; Prevotella; Proteomics; Rats; Rats, Wistar; Starch; Streptococcus pneumoniae; Sugar Alcohol Dehydrogenases; Transcriptome

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Brain; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Female; Humans; Inflammation; Interleukin-8; Intravital Microscopy; Male; Mental Status and Dementia Tests; Mice; Microglia; Middle Aged; Monocytes; Neutrophils; Pneumococcal Infections; Receptors, CCR2; Sepsis-Associated Encephalopathy

Streptococcus pneumoniae (Spn) is a common respiratory pathogen and a frequent cause of acute otitis media (AOM) in children. The first step in bacterial pathogenesis of AOM is the establishment of asymptomatic colonization in the nasopharynx. We studied Spn bacterial burden in conjunction with neutrophil recruitment and inflammatory gene transcription and cytokine secretion in samples of nasal wash collected from normal and otitis-prone children during health, viral upper respiratory infection without middle ear involvement (URI) and AOM. We found no significant associations between otitis-prone status and any of the measured parameters. However, Spn bacterial burden was significantly correlated with neutrophil recruitment, transcription of IL-8, TNF-α and SOD2, and secretion of TNF-α. We also found that transcription of IL-8 and TNF-α mRNA by neutrophils was significantly correlated with the secretion of these cytokines into the nasopharynx. We conclude that Spn bacterial burden in the NP is a major determinant of neutrophil recruitment to the NP and activity during URI and AOM, and that neutrophils are contributors to the secretion of IL-8 and TNF-α in the NP when the Spn burden is high.

Topics: Acute Disease; Asymptomatic Diseases; Bacterial Load; Cell Movement; Child, Preschool; Cytokines; Ear, Middle; Humans; Infant; Inflammation; Inflammation Mediators; Interleukin-8; Nasopharyngeal Diseases; Neutrophils; Otitis Media; Pneumococcal Infections; RNA, Messenger; Streptococcus pneumoniae; Superoxide Dismutase; Tumor Necrosis Factor-alpha

CXCL14 is a chemokine with an atypical, yet highly conserved, primary structure characterized by a short N terminus and high sequence identity between human and mouse. Although it induces chemotaxis of monocytic cells at high concentrations, its physiological role in leukocyte trafficking remains elusive. In contrast, several studies have demonstrated that CXCL14 is a broad-spectrum antimicrobial peptide that is expressed abundantly and constitutively in epithelial tissues. In this study, we further explored the antimicrobial properties of CXCL14 against respiratory pathogens in vitro and in vivo. We found that CXCL14 potently killed Pseudomonas aeruginosa, Streptococcus mitis, and Streptococcus pneumoniae in a dose-dependent manner in part through membrane depolarization and rupture. By performing structure-activity studies, we found that the activity against Gram-negative bacteria was largely associated with the N-terminal peptide CXCL141-13. Interestingly, the central part of the molecule representing the β-sheet also maintained ∼62% killing activity and was sufficient to induce chemotaxis of THP-1 cells. The C-terminal α-helix of CXCL14 had neither antimicrobial nor chemotactic effect. To investigate a physiological function for CXCL14 in innate immunity in vivo, we infected CXCL14-deficient mice with lung pathogens and we found that CXCL14 contributed to enhanced clearance of Streptococcus pneumoniae, but not Pseudomonas aeruginosa. Our comprehensive studies reflect the complex bactericidal mechanisms of CXCL14, and we propose that different structural features are relevant for the killing of Gram-negative and Gram-positive bacteria. Taken together, our studies show that evolutionary-conserved features of CXCL14 are important for constitutive antimicrobial defenses against pneumonia.

Topics: Adenosine Monophosphate; Amino Acid Sequence; Animals; Anti-Infective Agents; Cell Membrane; Chemokines, CXC; Chemotaxis; Disease Models, Animal; DNA, Bacterial; Interleukin-8; Lung; Mice; Mice, Knockout; Microbial Sensitivity Tests; Models, Molecular; Myeloblastin; Peptide Fragments; Permeability; Pneumococcal Infections; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Proteolysis; Respiratory Tract Infections; Streptococcus pneumoniae

Influenza A virus (IAV) predisposes individuals to secondary infections with the bacterium Streptococcus pneumoniae (the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM.

Topics: Animals; Inflammation; Influenza A virus; Interleukin-6; Interleukin-8; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Otitis Media; Pneumococcal Infections; Viral Load

The success of Streptococcus pneumoniae (the pneumococcus) as a pulmonary pathogen is related to its restriction of innate immune responses by respiratory epithelial cells. The mechanisms used to overcome this restriction are incompletely elucidated. Pulmonary chemokine expression involves complex cellular and molecular networks, involving the pulmonary epithelium, but the specific cellular interactions and the cytokines that control them are incompletely defined. We show that serotype 2 or 4 pneumococci induce only modest levels of CXCL8 expression from epithelial cell lines, even in the absence of a polysaccharide capsule. In contrast, coculture of A549 cells with the macrophage-like THP-1 cell line, differentiated with vitamin D, or monocyte-derived macrophages enhanced CXCL8 release. Supernatants from the THP-1 cell line prime A549 cells to release CXCL8 at levels similar to cocultures. Interleukin-1Ra (IL-1Ra) inhibits CXCL8 release from cocultures and reduces the activity of macrophage-conditioned media, but inhibition of tumor necrosis factor alpha (TNF-α) had only a minimal effect on CXCL8 release. Release of IL-1β but not TNF-α was upregulated in cocultures. IL-1 type 1 receptor knockout C57BL/6 and BALB/c mice confirmed the importance of IL-1 signaling in CXC chemokine expression and neutrophil recruitment in vivo. In fulminant disease, increased IL-1 signaling resulted in increased neutrophils in the airway and more invasive disease. These results demonstrate that IL-1 is an important component of the cellular network involving macrophages and epithelial cells, which facilitates CXC chemokine expression and aids neutrophil recruitment during pneumococcal pneumonia. They also highlight a potential clinical role for anti-IL-1 treatment to limit excessive neutrophilic inflammation in the lung.

Topics: Animals; Cell Line; Coculture Techniques; Culture Media, Conditioned; Epithelial Cells; Female; Humans; Interleukin-1beta; Interleukin-8; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Pneumococcal Infections; Receptors, Interleukin-1; Streptococcus pneumoniae

Surface-exposed pneumococcal virulence proteins pneumococcal surface protein A (PspA) and pneumococcal surface protein C (PspC) play important roles in the pathogenesis of invasive pneumococcal diseases. Human neutrophils are principle antimicrobial effector cells of the innate and adaptive immune systems. In this study, we investigated the effects of PspA and PspC on the up-regulation of chemokine CXCL8 in human neutrophils, and characterized the underlying intracellular signaling pathways. Both PspA and PspC were found to induce the release of newly synthesized CXCL8. Synergistic effect was observed in the combined treatment of PspA and PspC on the release of CXCL8. Products from PspA-deficient or PspC-deficient mutant pneumococcus that did not express PspA or PspC induced significantly less release of CXCL8 than wild type pneumococcus. Both PspA and PspC could activate p38 MAPK and NF-κB pathways in neutrophils, while inhibition of NF-κB and p38 MAPK could suppress the release of CXCL8 from neutrophils induced by PspA and PspC. Together, our results demonstrated that the induction of CXCL8 in human neutrophils activated by PspA and PspC was regulated by p38 MAPK and NF-κB pathways.

Topics: Bacterial Proteins; Cells, Cultured; Gene Deletion; Host-Pathogen Interactions; Humans; Interleukin-8; Neutrophils; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pneumococcal Infections; Signal Transduction

Chemokines play an important role in the recruitment and regulation of leukocyte traffic during bacterial infection. The aims of this study were to investigate the chemokine response to invasive pneumococcal disease (IPD) and to examine the influence of HIV infection on the chemokine response, pneumococcal bacterial loads, and outcome.. We prospectively studied 95 children with IPD, and blood and cerebrospinal fluid (CSF) samples were taken at admission for the determination of chemokines, interferon-gamma (IFNgamma), and pneumococcal bacterial loads.. Plasma CXCL8 and CCL2, CSF CXCL8 and CCL4, and IFNgamma were significantly higher in HIV-infected children than in HIV-uninfected children. Blood and CSF pneumococcal bacterial loads correlated with plasma and CSF chemokines, respectively, and were higher in HIV-infected children compared with HIV-uninfected children. Among HIV-infected children, plasma concentrations of CXCL8 and CCL2 were significantly higher in nonsurvivors than in survivors, but CCL5 was significantly lower. HIV-infected and HIV-uninfected children with IPD had higher concentrations of chemokines (except CCL5) than acutely ill HIV-infected and HIV-uninfected children with no detectable bacterial infection. Male gender and low plasma CCL2 concentrations were shown to be independently associated with survival.. Chemokines, in particular CCL2, are associated with survival in IPD and correlate with pneumococcal bacterial loads, disease presentation, and outcome.

Topics: Adolescent; Anti-Bacterial Agents; Chemokine CCL2; Chemokine CCL4; Chemokine CCL5; Chemokines; Chemokines, CC; Child; Child, Preschool; DNA, Bacterial; HIV Infections; Humans; Infant; Interferon-gamma; Interleukin-8; Pneumococcal Infections; Polymerase Chain Reaction; Streptococcus pneumoniae; Survival Analysis

The aim of this study was to test the hypothesis that elevated lipopolysaccharide binding protein (LBP) serum concentration is a useful marker in the early diagnosis of invasive bacterial infection in children. We measured LBP in serum and cerebrospinal fluid (CSF) of children with proven invasive infection caused by Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis.. Samples were collected from 39 children (aged 2 months to 17 years) with bacterial sepsis (n = 19) or meningitis (n = 20). Bacterial infection was diagnosed when a blood or CSF culture was positive and clinical signs of invasive infection were present. The control group consisted of serum (n = 60) and CSF (n = 19) samples from children with neurologic disease, juvenile idiopathic arthritis or viral infection. In 10 patients with bacterial infection, follow-up samples (24 and 48 hours) were available. LBP values were measured by an immunochemiluminescence analyzer (IMMULITE; DPC Biermann, Bad Nauheim, Germany) and compared with tumor necrosis factor-alpha and interleukin-8 concentrations.. The median LBP serum concentrations in patients with bacterial infection were markedly elevated compared with the control groups (45.0 [33.1-55.2] versus 8.3 [6.8-10.1] microg/mL [median and 5-95% confidence interval]; P < 0.0001). Follow-up serum values of LBP were persistently elevated despite adequate antibiotic treatment, whereas tumor necrosis factor-alpha and interleukin-8 concentrations decreased. In contrast, LBP concentrations in the CSF were below the detection limit of 0.5 microg/mL in 67% of patients with bacterial meningitis (median <0.5 microg/mL), whereas tumor necrosis factor-alpha and interleukin-8 levels were highly elevated.. LBP serum concentration is elevated in serum of children with invasive bacterial infection and could be a promising diagnostic marker.

Topics: Acute-Phase Proteins; Adolescent; Biomarkers; Carrier Proteins; Cerebrospinal Fluid; Child; Child, Preschool; Haemophilus Infections; Haemophilus influenzae; Humans; Immunoassay; Infant; Interleukin-8; Luminescent Measurements; Membrane Glycoproteins; Meningitis, Bacterial; Meningococcal Infections; Neisseria meningitidis; Pneumococcal Infections; Sepsis; Serum; Streptococcus pneumoniae; Time Factors; Tumor Necrosis Factor-alpha

HIV-infected adults are highly susceptible to pneumococcal disease.. To examine if alveolar macrophages from HIV-infected subjects exhibited a failure of cytokine production in response to Streptococcus pneumoniae in vitro.. Case-control comparison of alveolar macrophages from 11 HIV-infected and 13 non-infected adults.. Type 1 opsonized S. pneumoniae were used to challenge the alveolar macrophages in vitro. Cell supernatant fluid was collected from unstimulated cells, and cells challenged with bacteria for 0, 6, 12 and 24 h. Cytokine production (interleukins 1beta, 6 and 8) was measured in all fluids using an enzyme-linked immunosorbent assay.. All the cytokines tested increased over time in both HIV-infected and uninfected subjects. Interleukin-8 release was significantly lower in HIV-infected than in non-HIV-infected subjects (P = 0.02).. Reduced interleukin-8 production may result in decreased neutrophil recruitment, and hence increased susceptibility to pneumococcal infection in HIV-infected subjects.

Topics: Adult; Case-Control Studies; Female; HIV Infections; Humans; Interleukin-8; Macrophages, Alveolar; Male; Middle Aged; Pneumococcal Infections; Streptococcus pneumoniae

Differences in inflammatory responses in human adult whole blood to live pneumococcal serotypes 3, 7F, 9V and 23F were investigated. Using flow cytometry and ELISA, oxidative burst, expression of activation markers CD11b/CD18, and in-vitro production of tumour necrosis factor-alpha, interleukin-6 (IL-6) and interleukin-8 were measured. There was no significant difference between the serotypes regarding any of the variables investigated, although there was a trend towards higher concentrations of IL-6 induced by serotypes 9V and 23F. In the present experimental model, the serotypes of Streptococcus pneumoniae shown previously to cause different degrees of inflammation were found to cause a similar inflammatory response in human whole blood.

Topics: CD11b Antigen; CD18 Antigens; Cytokines; Humans; Inflammation; Interleukin-6; Interleukin-8; Pneumococcal Infections; Respiratory Burst; Serotyping; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Pneumolysin is an important virulence factor of Streptococcus pneumoniae, interacting with the membranes of host cells to elicit a multitude of inflammatory responses. We used cDNA microarrays to identify genes which are responsive to S. pneumoniae in a pneumolysin-dependent and -independent fashion. The THP-1 human monocytic cell line was coincubated for 3 h with medium alone, with the virulent type 2 S. pneumoniae strain D39, or with the isogenic strain PLN, which does not express pneumolysin. RNA was isolated from the monocytes and hybridized on cDNA microarrays. Of 4,133 genes evaluated, 142 were found to be responsive in a pneumolysin-dependent fashion, whereas 40 were found to be responsive independent of pneumolysin. Genes that were up-regulated in cells exposed to D39 relative to those exposed to PLN included genes encoding proteins such as mannose binding lectin 1, lysozyme, alpha-1 catenin, cadherin 17, caspases 4 and 6, macrophage inflammatory protein 1beta (MIP-1beta), interleukin 8 (IL-8), monocyte chemotactic protein 3 (MCP-3), IL-2 receptor beta (IL-2Rbeta), IL-15 receptor alpha (IL-15Ralpha), interferon receptor 2, and prostaglandin E synthase. Down-regulated genes included those encoding complement component receptor 2/CD21, platelet-activating factor acetylhydrolase, and oxidized low-density lipoprotein receptor 1 (OLR1). Pneumolysin-independent responses included down-regulation of the genes encoding CD68, CD53, CD24, transforming growth factor beta2, and signal transducers and activators of transcription 1. These results demonstrate the striking effects of pneumolysin on the host cell upon exposure to S. pneumoniae.

Topics: Bacterial Proteins; Chemokine CCL4; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Gene Expression Regulation; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Monocytes; Oligonucleotide Array Sequence Analysis; Pneumococcal Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Streptococcus pneumoniae; Streptolysins; Tumor Cells, Cultured

This pilot study was designed to determine the serum cytokine profile of acute otitis media (AOM) due to Streptococcus pneumoniae and the impact of clarithromycin (Abbott Laboratories, Inc). Serum levels of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), IL-6, and IL-8 were measured at diagnosis and 3 to 5 days after start of antibiotic treatment in 10 patients (mean age, 18.3 +/- 13.9 months) who had middle ear fluid culture positive for S. pneumoniae. The mean concentrations of all cytokines were elevated at diagnosis of AOM compared to levels in healthy controls, yet only IL-6 reached statistical significance (P = 0.05). IL-6 showed a statistically significant decrease in mean serum concentration at visit 2 (P = 0.03). IL-8 displayed a similar pattern to IL-6, but the difference between samples from day 1 and day 2 did not reach statistical significance. The cytokines IL-1 beta and TNF-alpha appear to be elevated in the serum of patients with S. pneumoniae AOM, but there was no significant change between mean serum levels obtained pre- and postinitiation of antibiotic treatment in the time frame studied. The results suggest a systemic inflammatory response as evidenced by increased IL-6. A significant decrease of IL-6 and improvement of clinical symptoms were observed. Determining cytokine levels, especially IL-6, in AOM could offer a powerful tool for objective assessment of response to treatment, minimizing unnecessary treatment of asymptomatic children who may still have some otoscopic findings suggestive of AOM at follow-up visits.

Topics: Biomarkers; Case-Control Studies; Child, Preschool; Clarithromycin; Follow-Up Studies; Humans; Infant; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; Otitis Media with Effusion; Pilot Projects; Pneumococcal Infections; Time Factors; Tumor Necrosis Factor-alpha

The Streptococcus pneumoniae cell-wall components peptidoglycan and lipoteichoic acid activate Toll-like receptor 2 (TLR2), which transduces an inflammatory response. After exposure to penicillin, type 2 S. pneumoniae strain D39, but not the isogenic autolysin-deficient mutant AL2, induced significantly enhanced interleukin-8 promoter activity in TLR2-transfected HeLa cells. Lag-phase D39 exhibited enhanced TLR2 activation after exposure to penicillin at levels below the minimum inhibitory concentration (MIC); in contrast, early log-phase S. pneumoniae were most active when exposed to the MIC. This enhancement was not ablated by heat treatment but was attenuated by autolysin inhibitors. The antimicrobial activity of moxifloxacin and erythromycin was not associated with TLR2 activation by S. pneumoniae. These data show that penicillin treatment of S. pneumoniae releases proinflammatory cell-wall components that activate TLR2 and that this activity is dependent on autolysin, the growth phase of the organism, and the antibiotic concentration.

Topics: Anti-Infective Agents; Aza Compounds; Choline; Colony Count, Microbial; Enzyme Inhibitors; Erythromycin; Ethanolamine; Fluoroquinolones; HeLa Cells; Humans; Interleukin-8; Membrane Glycoproteins; Moxifloxacin; N-Acetylmuramoyl-L-alanine Amidase; Penicillins; Pneumococcal Infections; Quinolines; Receptors, Cell Surface; Streptococcus pneumoniae; Toll-Like Receptor 2; Toll-Like Receptors; Transfection

Pneumococcal capsular polysaccharide (PS) vaccines induce type-specific immunoglobulin M (IgM), IgG, and IgA. Type-specific IgG to the PS is sufficient to confer protection against the homologous serotype of the pneumococcus, but the efficacies of type-specific IgM and IgA are less well understood. We examined the in vitro activities and efficacies in mice of two human monoclonal antibodies (MAbs) to type 8 PS, NAD (IgA) and D11 (IgM). MAb-mediated opsonophagocytic killing was evaluated after coculture of type 8 pneumococci with human polymorphonuclear cells (PMNs), type-specific or control MAbs, and human complement sources. The effects of the MAbs on PMN interleukin-8 (IL-8) and IL-6 secretion were determined in supernatants from cocultures containing pneumococci and PMNs by enzyme-linked immunosorbent assay. MAb efficacy was determined in an intratracheal model of type 8 infection in mice with classical complement pathway deficiency. Both MAbs were protective in 100% of infected mice. Neither MAb promoted a significant amount of killing of type 8 pneumococci compared to its isotype control MAb. Both type-specific MAbs mediated complement-dependent modulation of PMN IL-8 secretion, with increased secretion at effector/target (E:T) ratios of 500:1 and 50:1 and reduced secretion at 1:5. Trypan blue staining revealed that PMNs cocultured with D11 were less viable at an E:T ratio of 1:5 than PMNs cocultured with the control MAb. PMN IL-6 secretion was increased by both type-specific and control MAbs. These results suggest that certain type-specific IgM and IgAs might contribute to host defense by modulation of the inflammatory response to pneumococci.

Topics: Animals; Antibodies, Bacterial; Antibodies, Monoclonal; Antibody Specificity; Coculture Techniques; Gene Expression Regulation; Immunoglobulin A; Immunoglobulin Isotypes; Immunoglobulin M; Interleukin-8; Mice; Molecular Sequence Data; Neutrophils; Opsonin Proteins; Phagocytosis; Pneumococcal Infections; Polysaccharides, Bacterial; Streptococcus pneumoniae

Human immunodeficiency virus (HIV)-infected patients are at increased risk of contracting bacterial infections, mainly pneumonia. Despite this, little is known about immunopathogenic mechanisms in HIV-related bacterial pneumonia. This paper investigates the presence of the neutrophil chemotactic mediators, interleukin-8 (IL_8) and leukotriene B4 (LTB4), in bronchoalveolar lavage (BAL) fluid from 27 HIV-infected patients with bacterial pneumonia. Significantly elevated levels of IL-8 were found in BAL fluid of patients with bacterial pneumonia [529 pg ml-1 (296-1161 pg ml-1)] compared to matched patients with Pneumocystis carinii pneumonia (PCP) [59 pg ml-1 (42-254 pg ml-1)] and healthy controls [58 pg ml-1 (37-82 pg ml-1)]. Levels of LTB4 were not elevated during bacterial pneumonia when compared to PCP patients and healthy controls. Furthermore, a positive correlation was found between IL-8 levels in BAL fluid and relative BAL neutrophilia (r = 0.60, P = 0.001) in bacterial pneumonia. In conclusion, elevated IL-8 levels in BAL fluid were found in patients suffering from bacterial pneumonia, which may account for the influx of neutrophils to the lung, whereas LTB4 appears not to be an important chemotactic factor in this setting.

Topics: Bronchoalveolar Lavage Fluid; CD4 Lymphocyte Count; Chemotaxis, Leukocyte; Haemophilus Infections; HIV Infections; Humans; Interleukin-8; Leukotriene B4; Neutrophils; Pneumococcal Infections; Pneumonia, Bacterial; Pneumonia, Pneumocystis; Staphylococcal Infections

Interleukin-8 (IL-8), a potent inflammatory mediator that is thought to control leukocyte recruitment and activation during inflammatory reactions, has been implicated in a variety of inflammatory diseases. Recent studies in our laboratory have demonstrated the presence of IL-8 in chronically inflamed human middle ear effusions. These data have led us to hypothesize that IL-8 is responsible for the leukocyte recruitment seen in otitis media. Because the effect of IL-8 on the middle ear mucosa has not been investigated and therefore its role in middle ear inflammation is not known, we investigated the ability of IL-8 to directly induce inflammation in the murine middle ear. For these studies, ICR mice were used to test the hypothesis that IL-8 could directly induce inflammation in the middle ear. Murine middle ears received 8-mL transtympanic injections of human IL-8 (25 mg/mL) in saline, heat-killed Streptococcus pneumoniae (1 x 10(8)/mL), or normal saline. Temporal bones were removed at 1, 4, 8, 24, and 48 hours, decalcified, and processed for histologic examination. Noninjected murine temporal bones served as controls. Normal saline-injected ears demonstrated little to no change as compared with temporal bones from noninjected ears. IL-8-injected ears histologically demonstrated thickening of the epithelial layer and subepithelial space (SES), with inflammatory cell infiltration in the SES peaking at 4 to 8 hours and resolving by 48 hours. Bacteria-injected ears demonstrated findings similar to, although not as extensive as, those found in IL-8-injected ears (i.e., inflammatory reactions peaked at 8 to 24 hours and resolved by 72 hours). Our results demonstrate that IL-8 is a potent inducer of middle ear inflammation and support the concept that IL-8 may be one of the key cytokines responsible for the leukocyte accumulation and activation seen in otitis media.

Topics: Animals; Female; Humans; Interleukin-8; Lymphocyte Activation; Mice; Mice, Inbred ICR; Neutrophils; Otitis Media; Pneumococcal Infections; Temporal Bone

Because interleukin 8 (IL-8) is a potent neutrophil chemotactic and activating cytokine, we investigated IL-8 production in relation to neutrophil migration and elastase release in the human lung during unilateral community-acquired pneumonia (CAP). In 17 patients, the local response in the involved lung was compared with that in the contralateral, noninvolved lung, and with the systemic response. Eight healthy volunteers served as controls. IL-8, total neutrophil elastase (NE), free elastase activity, alpha 1-antitrypsin (alpha 1-AT), and total leukocyte and neutrophil counts were evaluated in bronchoalveolar lavage fluids (BALF). Mean IL-8 concentrations in BALF from the involved lungs of the patients were significantly greater than those in BALF from the noninvolved lung or from controls (p < or = 0.001). By contrast, the serum IL-8 concentration was not different in patients and in controls. Total NE and alpha 1-AT concentrations were increased in BALF from the involved lung as compared with the noninvolved lung or controls (p < or = 0.001). The elastase-inhibitory capacity of alpha 1-AT in BALF was impaired in the involved lung of seven of the 14 patients as compared with the controls, leading to free elastase activity in the involved lung of all patients with CAP. Plasma total NE concentrations were significantly greater in the CAP patients than in the controls. IL-8 concentrations in BALF correlated positively with total leukocyte counts, absolute numbers and percentages of neutrophils, total NE concentrations, and free elastase activity. Our results suggest that during unilateral CAP, locally produced IL-8 may trigger neutrophil accumulation and activation, thus contributing to a local elastase/antielastase imbalance within the site of infection.

Topics: Adolescent; Adult; Aged; Albumins; alpha 1-Antitrypsin; Bronchoalveolar Lavage Fluid; Community-Acquired Infections; Data Interpretation, Statistical; Female; Haemophilus Infections; Humans; Immunoenzyme Techniques; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Lung; Male; Meningococcal Infections; Middle Aged; Neutrophils; Pancreatic Elastase; Pneumococcal Infections; Pneumonia, Bacterial