Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0348321 (Haemophilus)
 15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of trovafloxacin, ciprofloxacin and ceftriaxone on cytokine production of human peripheral blood mononuclear cells (PBMCs) was examined. PBMC responses were measured after stimulation with lipopolysaccharide (LPS), lipoteichoic acid (LTA) or killed or viable Streptococcus pneumoniae and Haemophilus influenzae. Trovafloxacin inhibited the production of tumour necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 and IL-8 by PBMCs after stimulation with either LPS or LTA by 83%. Similar inhibition occurred in PBMCs incubated with killed or live bacteria and trovafloxacin, but not with ciprofloxacin or ceftriaxone. The relevance of this in vitro observation was explored by examining TNF-alpha and IL-6 responses in trovafloxacin-treated mice. Serum concentrations of both cytokines 1 h after LPS challenge were 95% less than serum concentrations in mice that were not given trovafloxacin. Reverse transcription- polymerase chain reaction studies of the mechanisms determining cytokine down-regulation demonstrated that trovafloxacin reduced TNF-alpha, IL-1beta and IL-6 mRNA to levels similar to those of unstimulated cells. These observations indicate that trovafloxacin can consistently and significantly reduce production of cytokines that play an important role in sepsis. In vitro, this effect can occur in the presence of bacteriolysis and is associated with inhibition of transcription of cytokine genes.
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PMID:The effect of three broad-spectrum antimicrobials on mononuclear cell responses to encapsulated bacteria: evidence for down-regulation of cytokine mRNA transcription by trovafloxacin. 1110 11

Bony tissues are integral parts of the function of the middle ear and the protection of adjacent vital structures. To explore the reaction of middle ear bone to acute otitis media, rats were challenged with Streptococcus pneumoniae and Haemophilus influenzae. Local changes were monitored for up to 1 month. After reverse transcription, competitive polymerase chain reaction was used to determine the expression levels of two molecular markers of bone formation, osteocalcin and procollagen I, and the two cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, in the bone. Middle ear bone responded rapidly to bacterial challenge, and the reaction depended upon the causative agent. On day 1, IL-6 and TNF-alpha transcripts were detected in the bone from all middle ears. After a short period of decreased expression of osteocalcin, during which the otitis diagnosis could not be made clinically, the levels of bone formation markers increased dramatically. The maximum levels of these markers were reached on days 6 and 14 for animals challenged with H. influenzae and pneumococci, respectively. Infections induced by pneumococci had a longer duration, and after the initial phase the production of osteocalcin and procollagen transcript were significantly higher in the pneumococcus-infected animals. The results indicate that even in an uncomplicated infection, the bone of the bulla reacts to an acute otitis media with a short period of inhibited osteoblast activity followed by a longer period of new bone formation.
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PMID:Expression of molecular markers for bone formation increases during experimental acute otitis media. 1127 36

To define the role of nontypeable Haemophilus influenzae (NTHI) lipooligosaccharide (LOS) in the induction of proinflammatory cytokine gene expression during otitis media, we compared the abilities of formalin-killed NTHI strain 2019 and its LOS htrB and rfaD mutants to stimulate human middle ear epithelial (HMEE) cell cytokine and chemokine gene expression and production in vitro. Strain DK-1, an rfaD gene mutant, expresses a truncated LOS consisting of only three deoxy-D-manno-octulosonic acid residues, a single heptose, and lipid A. Strain B29, an isogenic htrB mutant, possesses an altered oligosaccharide core and an altered lipid A. HMEE cells were incubated with formalin-killed NTHI 2019, B29, or DK-1. The supernatants and the cells were collected at 2, 4, 8, and 24 h after stimulation. Expression of genes for the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin lbeta (IL-1beta), and IL-6 and for the chemokines macrophage inflammatory protein 1beta (MIP-1beta), monocyte chemotactic peptide 1 (MCP-1), and IL-8 was quantitated by real-time PCR. NTHI B29 did not significantly stimulate any cytokine or chemokine mRNA expression in HMEE cells. In striking contrast, NTHI 2019 induced up to 105-, 139-, and 187-fold increases in HMEE cell expression of IL-1beta, TNF-alpha, and MIP-1beta, respectively (P < 0.01 [2019 versus B29]). NTHI 2019 also induced upregulation of IL-8, IL-6, and MCP-1 mRNA expression (by 26-, 44-, and 14-fold, respectively [P < 0.05 (2019 versus B29)]). The significant induction of cytokine genes was confirmed by quantitating the secretion of cytokines in culture supernatants with an enzyme-linked immunosorbent assay. There were no significant differences in mRNA expression of IL-8, IL-6, and MCP-1 between the 2019- and DK-1-treated groups. The low levels of gene transcripts observed after incubation of HMEE cells with B29 indicate that products of the disrupted NTHI htrB LOS gene may play a major role in induction of these particular inflammatory mediators.
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PMID:Expression of cytokine and chemokine genes by human middle ear epithelial cells induced by formalin-killed Haemophilus influenzae or its lipooligosaccharide htrB and rfaD mutants. 1134 30

We investigated the role of cytokines in differences in histopathologic changes in the lung between bronchopneumonia caused by non-encapsulated Haemophilus influenzae strain 770235f(0)b(0)and systemic disease caused by type b H. influenzae strain 770235f(0)b(+). Tumour necrosis factor-alpha (TNF-alpha), interleukin-(IL)-6 and IL-1 beta levels in bronchoalveolar lavage fluid (BALF) samples of mice infected with strain 770235f(0)b(0)were higher than in those infected with strain 770235f(0)b(+)until 24 h post-infection. Serum IL-6 rapidly increased in strain 770235f(0)b(0)infection after 72 h post-infection. Serum TNF-alpha level in strain 770235f(0)b(0)infection appeared earlier than in strain 770235f(0)b(+)infection. IL-1 beta production in strain 770235f(0)b(+)infection was later than in strain 770235f(0)b(0)infection. Moreover, a biphasic concentration pattern of TNF-alpha and IL-6 was noted in BALF of mice with strain 770235f(0)b(0)infection.
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PMID:Lipoolygosaccharide indirectly enhances inflammatory lesions in lungs as a primary infection site by non-encapsulated and type B Haemophilus influenzae through production of cytokines. 1155 87

Toll-like receptors (TLRs) have been implicated in the regulation of host responses to microbial Ags. This study characterizes the role of TLR4 in the innate immune response to intrapulmonary administration of Haemophilus influenzae in the mouse. Two different strains of mice efficiently cleared aerosolized H. influenzae concurrent with a brisk elaboration of IL-1beta, IL-6, TNF-alpha, macrophage-inflammatory protein (MIP)-1alpha, and MIP-2 in bronchoalveolar lavage and a corresponding mobilization of intrapulmonary neutrophils. Congenic strains of mice deficient in TLR4 demonstrated a substantial delay in clearance of H. influenzae with diminished IL-1beta, IL-6, TNF-alpha, MIP-1alpha, and MIP-2 in bronchoalveolar lavage and a notable absence of intrapulmonary neutrophils. In TLR4-expressing animals, but not TLR4-deficient animals, TNF-alpha and MIP-1alpha expression was up-regulated in epithelial cells of the conducting airway in response to H. influenzae which was preceded by an apparent activation of the NF-kappaB pathway in these cells based on the findings of decreased overall IkappaB and an increase in its phosphorylated form. This study demonstrates a critical role of TLR4 in mediating an effective innate immune response to H. influenzae in the lung. This suggests that the airway epithelia might contribute to sensing of H. influenzae infection and signaling the innate immune response.
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PMID:Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. 1177 76

Conjugate vaccines consisting of the capsular polysaccharide (PS) of Haemophilus influenzae type b (Hib) covalently linked to carrier proteins, unlike pure PS, are immunogenic in infants and have significantly reduced Hib infections in the United States, but require multiple doses to induce protective anti-PS Ab titers. Hib-meningococcal outer membrane protein complex (OMPC) conjugate vaccine, however, elicits protective anti-PS Ab titers after one dose. We found that OMPC and Hib-OMPC engaged human Toll-like receptor 2 (TLR2) expressed in human embryonic kidney (HEK) cells, inducing IL-8 production, and engaged mouse TLR2 on bone marrow-derived dendritic cells, inducing TNF release. Hib conjugated to the carrier proteins CRM(197) and tetanus toxoid did not engage TLR2 on HEK or dendritic cells. Engagement of TLR2 by Hib-OMPC was MyD88 dependent, as Hib-OMPC-induced TNF production was ablated in MyD88 knockout (KO) mice. Hib-OMPC was significantly less immunogenic in TLR2 KO mice, inducing lower Hib PS IgG and IgM titers compared with those in wild-type mice. Splenocytes from OMPC-immunized TLR2 KO mice also produced significantly less IL-6 and TNF-alpha than those from wild-type mice. Hib-OMPC is unique among glycoconjugate vaccines by engaging TLR2, and the ability of Hib-OMPC to elicit protective levels of Abs after one dose may be related to TLR2-mediated induction and regulation of cytokines produced by T cells and macrophages in addition to the peptide/MHC II-dependent recruitment of T cell help commonly afforded by carrier proteins. TLR2 engagement by an adjuvant or carrier protein may be a useful strategy for augmentation of the anti-PS Ab response induced by glycoconjugate vaccines.
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PMID:Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. 1476 14

There are indications that bone regulatory and immune systems are closely related. Of special interest in this context is the acute otitis media (AOM), which mainly affects immunologically immature patients and, when complicated, involves bone tissue. To explore host responses in bone tissue during Haemophilus influenzae-induced AOM modified by amoxicillin, a rat model and PCR techniques were used. The treatment eradicated the bacteria and induced changes in the expression profile of osteocalcin, a bone formation marker. The maximum levels of osteocalcin transcripts in the treatment group were delayed by about a week. The mRNA levels never reached the same high levels as in the untreated animal group, but the downregulation was slow and entailed higher osteocalcin mRNA levels for a longer time period in the treated animals. The expression of IL-6 and TNF-alpha, two cytokines associated with bone resorption, remained unaffected by the amoxicillin treatment, whereas the downregulation of IL-10, with suppressive effects on bone resorption, was slower than that during the natural course. By comparing the host responses on the molecular level in different tissues during treated and untreated AOM, new approaches to how to minimize the risks of severe AOM complications may evolve.
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PMID:Effects of amoxicillin on cytokine and osteocalcin expression in bone tissue during experimental acute otitis media. 1503 40

The interactions of bacterial pathogens with cells of the human leptomeninges are critical events in the progression of meningitis. An in vitro model based on the culture of human meningioma cells was used to investigate the interactions of the meningeal pathogens Escherichia coli K1, Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae. A rank order of association with meningioma cells was observed, with N. meningitidis showing the highest levels of adherence, followed by E. coli, S. pneumoniae and H. influenzae. Neisseria meningitidis and H. influenzae did not invade meningioma cells or induce cell death, but induced a concentration-dependent secretion of inflammatory mediators. Neisseria meningitidis induced higher levels of IL-6, MCP-1, RANTES and GM-CSF than H. influenzae, but there was no significant difference in the levels of IL-8 induced by both pathogens. Streptococcus pneumoniae was also unable to invade meningioma cells, but low concentrations of bacteria failed to stimulate cytokine secretion. However, higher concentrations of pneumococci led to cell death. By contrast, only E. coli K1 invaded meningioma cells directly and induced rapid cell death before an inflammatory response could be induced. These data demonstrate that the interactions of different bacterial pathogens with human meningeal cells are distinct, and suggest that different intervention strategies may be needed in order to prevent the morbidity and mortality associated with bacterial meningitis.
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PMID:Different meningitis-causing bacteria induce distinct inflammatory responses on interaction with cells of the human meninges. 1510 96

To evaluate the early stages of the host response to chancroid bacterium Haemophilus ducreyi, we investigated the in vitro responses of monocyte-derived dendritic cells (DCs) and macrophages (MQs) to this pathogen and Haemophilus influenzae. The phagocytic activities and pro-inflammatory cytokine secretion profiles of the antigen-presenting cells (APCs) were analyzed after exposure to gentamycin-killed bacteria, H. ducreyi lipooligosaccharide (LOS), and purified cytolethal distending toxin (HdCDT). T-cell proliferation and cytokine release were examined after co-culturing isolated autologous CD4+ T cells with antigen-pulsed APCs. Both the DCs and MQs phagocytosed H. ducreyi and H. influenzae, as estimated by flow cytometry. All of the strains induced APC secretion of TNF-alpha, IL-6, IL-8, and IL-12, as measured by ELISA. Other human cells, particularly endothelial cells and fibroblasts, also produced cytokines when stimulated with these bacteria. Purified LOS at concentration 1 microg/ml induced two to threefold lower levels of cytokines than the whole bacteria, which indicates that other components are involved in immune activation. HdCDT inhibited partially the production of the aforementioned cytokines. High levels of IFN-gamma, but not of IL-4 and IL-13, were secreted by T cells after activation by either DCs or MQs that were pre-exposed to bacteria, indicating the Th1 nature of the immune response. The levels of T-cell proliferation induced by H. ducreyi were lower than those induced by H. influenzae. HdCDT-treated APCs did not display cytokine responses or T-cell proliferation. These results indicate that HdCDT intoxication, which results in progressive apoptosis of APCs, may hamper early stage immune responses.
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PMID:Interactions of Haemophilus ducreyi and purified cytolethal distending toxin with human monocyte-derived dendritic cells, macrophages and CD4+ T cells. 1548 36

Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children, characterized by inflammation mainly mediated by cytokines and chemokines. One of the most abundant components of the Hib outer membrane is the P2 porin, which has been shown to induce the release of several inflammatory cytokines. Synthetic peptides corresponding to loops L5, L6, and L7 activate JNK and p38 mitogen-activated protein kinase (MAPK) pathways, L7 being the most active peptide. Therefore, sequence-activity relationships and key residues were identified by elongating sequence to different extents, designing cyclic peptides, and performing an alanine scan of L7. The ability of mutant peptides to induce activation of signal transduction pathways and release of TNF-alpha and IL-6 has been determined, and, in conjunction with CD spectra, bioinformatics analysis, and molecular dynamics data, showed that 6 out of 8 amino acids contribute significantly to the overall activity. Molecular dynamics showed that L7 modifications increased loop rigidity and helicity after Gly6 mutation, thus, providing a possible structural explanation for observed loss of bioactivity. This work provides insights into essential molecular details of P2 that may impact on the pathogenesis of Hib infections where interruption of the signaling cascade could represent an attractive therapeutic strategy.
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PMID:Structural requirements for proinflammatory activity of porin P2 Loop 7 from Haemophilus influenzae. 1658 85


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