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Niels Høiby

Publications and source records attributed to Niels Høiby.

At least 19 recordsLinked to original sources
PubMed2006

Biological Trojan horse: Antigen 43 provides specific bacterial uptake and survival in human neutrophils.

Escherichia coli is a versatile pathogen causing millions of infections in humans every year. This bacterium can form multicellular aggregates when it expresses a self-associating protein, antigen 43 (Ag43), on its surface. We have discovered that Ag43-expressing E. coli cells are efficiently taken up by human defense cells, polymorphonuclear neutrophils (PMNs), in an opsonin-independent manner. Surprisingly, the phagocytosed bacteria were not immediately killed but resided as tight aggregates within the PMNs. Our observations indicate that Ag43-mediated uptake and survival in PMNs constitute a mechanism to subvert one of the primary defense mechanisms of the human body.

Adhesins, Bacterial↗
PubMed2006

Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study.

BACKGROUND: In cystic fibrosis (CF), chronic infection of the airways with Achromobacter xylosoxidans have become more frequent. The pathogenic role of this is yet unclear. METHODS: A retrospective case-control study of all patients chronically infected with A. xylosoxidans for at least 3 years. 15 patients (6 males) with chronic A. xylosoxidans infection were matched by age, FEV(1) and body mass index z-score to 15 controls (7 males) at the time of establishment of chronic infection. Clinical parameters of the groups were compared from the time of establishment of chronic infection until spring 2006, giving a follow-up time of 3-11 years. Chest X-rays taken 3 years prior to establishment of chronic infection and after 3 years of chronic infection were compared using a modified Brasfield score. Finally, strains from individual patients were analysed using PFGE to investigate possible cross-infection. RESULTS: The median slope of decline of FEV(1) in the case group changed from +3.1% to -0.5% predicted/year (p<0.002). In the control group, median slope of decline in FEV(1) changed from +1.5% to -0.4% predicted/year (n.s.). Median slope of decline in FVC in the case group changed from +3.5% to -0.5% predicted/year (p<0.002). In the control group, median slope of decline in FVC changed from +1.7% to +0.4% predicted/year (n.s.). No significant difference in the slopes of decline of FEV(1) or FVC was found between the case group and the control group at either time. Change in BMI z-score was calculated for each group before and during chronic infection. No difference was found between the groups at any time or within a group. Specific antibodies against A. xylosoxidans were measured in patients with chronic infection. Patients with rapidly increasing antibody levels showed significantly faster deterioration in FEV(1) (p<0.05) and FVC (p<0.02). Chest X-ray scores increased in 6 of 10 chronically infected patients and in 3 of 10 controls (n.s.). Eight patients harboured a common A. xylosoxidans strain, indicating either cross-infection or a common source. CONCLUSION: A. xylosoxidans may lead to a decline in lung function in a subgroup of chronically infected CF patients characterised by a rapid increase in specific precipitating antibodies. Cross-infection may possibly occur.

Achromobacter denitrificans↗
PubMed2006

Intranasal immunisation with conjugate vaccine protects mice from systemic and respiratory tract infection with Pseudomonas aeruginosa.

We tested intranasal application of anti-Pseudomonas conjugate vaccine in mice. Comparison of immunisation via the intra-muscular versus intranasal routes showed the induction of equivalent levels of specific serum IgG and IgG subclasses antibodies if cholera toxin was used as an adjuvant. In contrast, secretion of specific mucosal IgA antibodies in the upper respiratory tract was only observed after intranasal immunisation together with adjuvant. Systemic and mucosal immunity was also established via the intranasal route when CpG-containing oligonucleotides were used as adjuvant. The functionality of intranasally induced antibodies was proven in vitro by opsonophagocytosis and in vivo using the burn-wound sepsis and intra-tracheal lung infection models. These results demonstrate the feasibility of intranasal immunisation against P. aeruginosa with conjugate vaccine.

Administration, Intranasal↗
PubMed2006

OXA-type carbapenemases.

In recent years, the number of class D beta-lactamases with carbapenem-hydrolysing properties has increased substantially. Based on amino acid sequence identities, these class D or OXA-type carbapenemases are divided into eight distantly related groups, and they are only remotely related to other class D beta-lactamases. A putative ancestor to one of the plasmid-encoded OXA-type carbapenemases has been found. OXA-type carbapenemases are not integrated into integrons as gene cassettes like many class D oxacillinases, but most of the OXA-type carbapenemases are instead encoded by chromosomal genes. Some of these OXA-type carbapenemases are widely dispersed in Pseudomonas aeruginosa and especially in Acinetobacter baumannii. Although most of the OXA-type carbapenemases show only weak carbapenemase activity, carbapenem resistance may result from a combined action an OXA-type carbapenemase and a secondary resistance mechanism such as porin deficiencies or overexpressed efflux pumps. This article reviews the phylogeny and the genetic environments of the encoding genes and kinetic properties of the OXA-type carbapenemases.

Acinetobacter baumannii↗
PubMed2006

Early rise of anti-pseudomonas antibodies and a mucoid phenotype of pseudomonas aeruginosa are risk factors for development of chronic lung infection--a case control study.

P. aeruginosa is the most significant pathogen in CF lung disease. Chronic infection is preceded by a period of intermittent colonization. Early aggressive antimicrobial treatment at initial detection of P. aeruginosa in lower respiratory tract (LRT) secretions can prevent transition to chronic infection in approximately 80% of the patients, while the rest progress to chronic infection in spite of treatment. To analyze risk factors for development of chronic infection, a cohort of 89 CF patients free of chronic infection at the study period start was followed for 10 years. 28 of the patients (study group) developed chronic infection in spite of early treatment and 28 age-matched patients who did not (controls) were included in the analysis. During the 3 years period prior to onset of chronic infection, P. aeruginosa-positive cultures were more frequent in the study group than in the controls (2.2 vs. 0.5 per year, p<0.0001). Growth of mucoid strains of P. aeruginosa was more frequent in study group than in controls (11.5% vs. 0%, p<0.0001). Most important, specific anti-pseudomonal IgG serum antibodies were significantly higher in the study group than in controls (0.98 Elisa Units vs. 0.53, p=0.04) already 3 years prior to onset of chronic infection and increased 0.44 EU pr year in the study group but remained at the initial level in the control group (p<0.005). Occurrence of Aspergillus-positive cultures were significantly more frequent in the study group than in controls (p=0.01). The strongest risk factor for development of chronic P. aeruginosa infection was increasing levels of specific anti-pseudomonal antibodies, specifically of IgG1 and IgG4 subclass and total anti-Pseudomonas IgG, 3 years prior to onset of chronic infection, with odds ratio (OR) 8.9, 7.7 and 7.4, respectively (p<0.005), and growth of mucoid P. aeruginosa strains with OR of 7.4, p=0.006). Occurrence of Aspergillus was also a risk factor for developing chronic P. aeruginosa infection with the OR of 4.7 (p=0.008).

Adolescent↗
PubMed2006

Prehospital diagnostic and therapeutic management of otogenic Streptococcus pneumoniae meningitis.

Prehospital diagnostics and therapeutic management, as well as clinical and laboratory data from 57 consecutive cases with otogenic pneumococcal meningitis (OPM) in Denmark during a 2-y period (1999-2000) were studied by review of discharge and medical records including a questionnaire sent to the general practitioners responsible for the individual patient. 12 cases were <2 y of age, whereas the remaining 45 cases were >21 y of age. Fever (in 98%) and altered consciousness (in 98%), respectively, were significantly more frequent prehospital symptoms (median duration of symptoms: 2 d (1-4)) than earache (in 71%, p < 0.0001), tympanic perforation (in 38%, p < 0.0001), and back rigidity (in 25%, p < 0.0001) in OPM. Some 82% visited a physician before admission, and an otogenic focus was diagnosed in 57%, a myringotomy was performed in 12%, and antibiotic therapy was initiated in 29% of these cases. Prehospital antibiotic therapy was more likely to be initiated in patients where the physician found an otogenic focus compared to patients where an otogenic was not found (46% vs 6%, respectively, p = 0.01). However, <10% of cases with OPM were treated for otitis media with adequate dosing of antibiotics for more than 1 d based on pharmacodynamic estimates. The clinical course was more severe in adults than in children (e.g. need for assisted ventilation (61% vs 0%, respectively, p < 0.01), development of sequelae (75% vs 8%, respectively, p < 0.01) together with higher CSF WBC and CSF protein levels (3738 vs 1361 cells/microl and 3.8 vs 1.6 g/l, respectively, p < 0.01), whereas corticosteroids were more frequently given to children than to adults (55% vs 3%, p < 0.001). Prehospital antibiotic therapy was not significantly associated with a more favourable outcome of OPM (50% vs 60%, respectively, p = 0.73). In conclusion, our results suggest that an otogenic focus is as frequent in adults as in children with pneumococcal meningitis and that an otogenic examination should be performed on patients presenting with fever and altered consciousness. Moreover, OPM seems predominantly to occur in patients receiving no or inadequate antibiotic therapy for otitis media.

Acute Disease↗
PubMed2006

Effect of aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with cystic fibrosis.

BACKGROUND: Aerosolized recombinant human deoxyribonuclease (rhDNase I (Pulmozyme)) has previously been shown to increase pulmonary function and reduce exacerbations of respiratory symptoms in cystic fibrosis (CF) patients with moderate to severe reduction in pulmonary function. AIM: To analyse whether aerosolized Pulmozyme could reduce the number of bacterial infections in the lower respiratory airways of CF patients without chronic pulmonary infection. METHODS: Patients were randomized either to aerosolized Pulmozyme 2(1/2) mg once daily or to no rhDNase treatment. The study period was 1 y, and the study was blinded for the Department of Clinical Microbiology. RESULTS: Overall, the number of positive cultures was significantly higher in the untreated group (82%) compared with the treated group (72%) (p<0.05). The most striking difference was found for Staphylococcus aureus, with a prevalence of 30% in the untreated group compared with 16% in the treated group (chi2 test, p<0.0001). Pulmonary function (FEV1) in the treated group showed a significant increase of 7.3% compared to 0.9% in the untreated group (p<0.05). CONCLUSION: Long-term DNase treatment was beneficial to CF patients without chronic lower respiratory tract infection, leading to reduced demand for antibiotics and to improved lung function.

Administration, Inhalation↗
PubMed2005

[Ginseng modulates the immune response via its effect on cytokine production--secondary publication].

Ginseng has been shown to modulate the immune system. In this study, ginseng"s effects against chronic P. aeruginosa lung infection in animal models and its cytokine-modulating effects on leukocytes were investigated. Leukocytes cultured with ginseng produced more interleukin-12. Animal models treated with ginseng s.c. showed a much faster bacterial clearance, milder lung pathology, activation of phagocytes and a Th1 immune response. These results suggest that ginseng treatment induced a Th1-like immune response, which improved the pathologic course in our animal models.

Animals↗
PubMed2005

Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study.

BACKGROUND: In cystic fibrosis (CF), chronic endobronchial infection with Pseudomonas aeruginosa is a serious complication. Macrolides can increase lung function and weight in patients, and reduce exacerbations. METHODS: In 2001, we introduced long-term, low-dose azithromycin (AZ) treatment as an integral part of our routine treatment of these patients. Our study is an observational cohort study of all CF patients with chronic P. aeruginosa infection in our CF center comparing clinical parameters of the patients 12 months prior to treatment with the same values during 12 months of treatment. RESULTS: 45 patients (27 men, median age 29 years) completed 1-year treatment. Median weight increased from 63.1 kg in the pre-treatment period to 63.9 kg during treatment (p=0.01). Median slope of decline in lung function increased from pre-treatment FEV1 -4.1% and FVC -3.0% to +0.8% (p<0.001) and +1.6% (p=0.01), respectively. 90% of sputum samples contained mucoid P. aeruginosa before treatment, decreasing to 81% during treatment (p=0.003). Median CRP decreased from 6.2 mmol/l to 5.8 mmol/l (ns). CONCLUSION: Long-term, low-dose AZ treatment in adult CF patients with chronic P. aeruginosa infection is safe and reduces the decline in lung function, increases weight, and reduces the percentage of mucoid strains of P. aeruginosa in sputum samples.

Adolescent↗
PubMed2005

Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent.

The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis (CF) patients. P. aeruginosa colonizes the CF lungs by forming biofilm structures in the alveoli. In the biofilm mode of growth the bacteria are highly tolerant to otherwise lethal doses of antibiotics and are protected from bactericidal activity of polymorphonuclear leukocytes (PMNs). P. aeruginosa controls the expression of many of its virulence factors by means of a cell-cell communication system termed quorum sensing (QS). In the present report it is demonstrated that biofilm bacteria in which QS is blocked either by mutation or by administration of QS inhibitory drugs are sensitive to treatment with tobramycin and H2O2, and are readily phagocytosed by PMNs, in contrast to bacteria with functional QS systems. In contrast to the wild-type, QS-deficient biofilms led to an immediate respiratory-burst activation of the PMNs in vitro. In vivo QS-deficient mutants provoked a higher degree of inflammation. It is suggested that quorum signals and QS-inhibitory drugs play direct and opposite roles in this process. Consequently, the faster and highly efficient clearance of QS-deficient bacteria in vivo is probably a two-sided phenomenon: down regulation of virulence and activation of the innate immune system. These data also suggest that a combination of the action of PMNs and QS inhibitors along with conventional antibiotics would eliminate the biofilm-forming bacteria before a chronic infection is established.

Animals↗
PubMed2005

The MexGHI-OpmD multidrug efflux pump controls growth, antibiotic susceptibility and virulence in Pseudomonas aeruginosa via 4-quinolone-dependent cell-to-cell communication.

In Pseudomonas aeruginosa the production of multiple virulence factors depends on cell-to-cell communication through the integration of N-acylhomoserine lactone (AHL)- and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS)- dependent signalling. Mutation of genes encoding the efflux protein MexI and the porin OpmD from the MexGHI-OpmD pump resulted in the inability to produce N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-c12-hsl) and pqs and a marked reduction in n-butanoyl-L-homoserine lactone levels. Both pump mutants were impaired in growth and exhibited enhanced rather than reduced antibiotic resistance. Provision of exogenous PQS improved growth and restored AHL and virulence factor production as well as antibiotic susceptibility, indicating that the pump mutants retained their capacity to respond to PQS. RT-PCR analysis indicated that expression of the PQS biosynthetic genes, phnA and pqsA, was inhibited when the mutants reached stationary phase, suggesting that the pleiotropic phenotype observed may be due to intracellular accumulation of a toxic PQS precursor. To explore this hypothesis, double mexI phnA (unable to produce anthranilate, the precursor of PQS) and mexI pqsA mutants were constructed; the improved growth of the former suggested that the toxic compound is likely to be anthranilate or a metabolite of it. Mutations in mexI and opmD also resulted in the attenuation of virulence in rat and plant infection models. In plants, addition of PQS restored the virulence of mexI and opmD mutants. Collectively, these results demonstrate an essential function for the MexGHI-OpmD pump in facilitating cell-to-cell communication, antibiotic susceptibility and promoting virulence and growth in P. aeruginosa.

4-Butyrolactone↗
PubMed2005

Garlic blocks quorum sensing and promotes rapid clearing of pulmonary Pseudomonas aeruginosa infections.

The opportunistic human pathogen Pseudomonas aeruginosa is the predominant micro-organism of chronic lung infections in cystic fibrosis patients. P. aeruginosa colonizes the lungs by forming biofilm microcolonies throughout the lung. Quorum sensing (QS) renders the biofilm bacteria highly tolerant to otherwise lethal doses of antibiotics, and protects against the bactericidal activity of polymorphonuclear leukocytes (PMNs). It has been previously demonstrated that QS is inhibited by garlic extract. In this study, the synergistic effects of garlic and tobramycin, and PMNs activities have been evaluated. P. aeruginosa was grown in vitro in continuous-culture once-through flow chambers with and without garlic extract. The garlic-treated biofilms were susceptible to both tobramycin and PMN grazing. Furthermore, the PMNs showed an increase in respiratory burst activation, when incubated with the garlic-treated biofilm. Garlic extract was administered as treatment for a mouse pulmonary infection model. Mice were treated with garlic extract or placebo for 7 days, with the initial 2 days being prophylactic before P. aeruginosa was instilled in the left lung of the mice. Bacteriology, mortality, histopathology and cytokine production were used as indicators. The garlic treatment initially provoked a higher degree of inflammation, and significantly improved clearing of the infecting bacteria. The results indicate that a QS-inhibitory extract of garlic renders P. aeruginosa sensitive to tobramycin, respiratory burst and phagocytosis by PMNs, as well as leading to an improved outcome of pulmonary infections.

Animals↗
PubMed2005

Serum concentrations of GM-CSF and G-CSF correlate with the Th1/Th2 cytokine response in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection.

The inflammation in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa lung infection is dominated by polymorphonuclear neutrophils (PMNs). There seems to be a relationship between the PMN-dominated inflammation, pronounced antibody production and a Th2-dominated response. Apart from mobilizing monocytes and PMNs from the bone marrow, GM-CSF, G-CSF and IL-3 select subsets of dendritic cells, which subsequently induce distinct Th responses. Therefore, the present study examines the correlation between the mobilizing cytokines in serum and the Th responses. The IFN-gamma and IL-4 production by peripheral blood mononuclear cells, and the concentrations of GM-CSF and G-CSF in serum as well as lung function, were determined in 37 CF patients with and 6 CF patients without chronic P. aeruginosa lung infection. The GM-CSF/G-CSF ratio correlated both with the IFN-gamma production and good lung function. In addition, an inverse correlation between IL-3 and IFN-gamma was observed. The results indicate involvement of endogenous GM-CSF, G-CSF and IL-3 in the skewed Th response in CF, and change to a Th1-dominated response might be achieved with GM-CSF treatment.

Adolescent↗
PubMed2005

Pseudomonas aeruginosa AmpR is a global transcriptional factor that regulates expression of AmpC and PoxB beta-lactamases, proteases, quorum sensing, and other virulence factors.

In members of the family Enterobacteriaceae, ampC, which encodes a beta-lactamase, is regulated by an upstream, divergently transcribed gene, ampR. However, in Pseudomonas aeruginosa, the regulation of ampC is not understood. In this study, we compared the characteristics of a P. aeruginosa ampR mutant, PAOampR, with that of an isogenic ampR+ parent. The ampR mutation greatly altered AmpC production. In the absence of antibiotic, PAOampR expressed increased basal beta-lactamase levels. However, this increase was not followed by a concomitant increase in the P(ampC) promoter activity. The discrepancy in protein and transcription analyses led us to discover the presence of another chromosomal AmpR-regulated beta-lactamase, PoxB. We found that the expression of P. aeruginosa ampR greatly altered the beta-lactamase production from ampC and poxB in Escherichia coli: it up-regulated AmpC but down-regulated PoxB activities. In addition, the constitutive P(ampR) promoter activity in PAOampR indicated that AmpR did not autoregulate in the absence or presence of inducers. We further demonstrated that AmpR is a global regulator because the strain carrying the ampR mutation produced higher levels of pyocyanin and LasA protease and lower levels of LasB elastase than the wild-type strain. The increase in LasA levels was positively correlated with the P(lasA), P(lasI), and P(lasR) expression. The reduction in the LasB activity was positively correlated with the P(rhlR) expression. Thus, AmpR plays a dual role, positively regulating the ampC, lasB, and rhlR expression levels and negatively regulating the poxB, lasA, lasI, and lasR expression levels.

Bacterial Proteins↗