Regine Landmann | University of Basel, Switzerland (original) (raw)

Papers by Regine Landmann

Journal of Neuroimmunology, 2009

TLR2 signaling participates in the pathogenesis of pneumococcal meningitis. In infant rats, the T... more TLR2 signaling participates in the pathogenesis of pneumococcal meningitis. In infant rats, the TLR2 agonist Pam 3 CysSK 4 was applied intracisternally (0.5 μg in 10 μl saline) alone or after induction of pneumococcal meningitis to investigate the effect of TLR2 activation on cerebrospinal fluid (CSF) inflammation and hippocampal apoptosis. A dose effect of Pam 3 CysSK 4 on apoptosis was investigated by intracisternal application of 0.5 μg in 10 μl saline and 40 μg in 20 μl saline. Pam 3 CysSK 4 neither induced apoptosis in shamoperated mice nor aggravated apoptosis in acute infection. However, Pam 3 CysSK 4 induced pleocytosis, TNF-α and MMP-9 in CSF in sham-infection but not during acute meningitis. We conclude that TLR2 signaling triggered by Pam 3 CysSK 4 at a dosage capable to induce a neuroinflammatory response does not induce hippocampal apoptosis in the infant rat model of experimental pneumococcal meningitis.

Infection and Immunity, 1996

Membrane CD14 is involved in lipopolysaccharide (LPS)-induced monocyte activation; it binds LPS, ... more Membrane CD14 is involved in lipopolysaccharide (LPS)-induced monocyte activation; it binds LPS, and antibodies against CD14 block the effects of low-dose LPS. It is unknown how LPS regulates its own receptor CD14 in vitro. Therefore, we investigated the effects of LPS on CD14 mRNA and membrane and soluble CD14 (mCD14 and sCD14, respectively) in human monocytes and macrophages. No changes were observed during the first 3 h of LPS stimulation. After 6 to 15 h, LPS weakly reduced CD14 mRNA and mCD14 and transiently enhanced sCD14 release. A 2-day incubation with LPS caused increases in the levels of CD14 mRNA (2-fold), mCD14 (2-fold), sCD14 (1.5-fold), and LPS-fluorescein isothiocyanate binding (1.5-fold); a 5-h incubation with LPS was sufficient to induce the late effects on mCD14 and sCD14. The maximal effect on mCD14 and sCD14 was reached with > or = 1 ng of LPS per ml; the proportional distribution of the two sCD14 isoforms was not modified by LPS. Besides rough and smooth LPS,...

Infection and Immunity, 1998

The glycoprotein CD14 acts as a receptor for lipopolysaccharide (LPS), either when anchored in th... more The glycoprotein CD14 acts as a receptor for lipopolysaccharide (LPS), either when anchored in the myeloid cell membrane (mCD14) or as a soluble molecule (sCD14) in serum. sCD14-LPS complexes activate cells devoid of mCD14. However, the role of sCD14 independent of LPS is unknown. Therefore, the effect of sCD14 on monocyte functions was investigated in the monocytic cell lines THP1 and Mono Mac 6 and in fresh human monocytes. Under serum-free conditions, endotoxin-free human recombinant sCD14(1-348), (rsCD14(1-348)) induced tumor necrosis factor alpha (TNF-alpha). The TNF-alpha effect was stronger in THP1 cells than in Mono Mac 6 cells or monocytes. It was dose dependent, with a maximum at 1 microg/ml, and time dependent, with a maximum after 2 h. sCD14 purified from urine had the same cytokine-activating capacity. In contrast, C-terminally truncated rsCD14(1-152) was inactive. The rsCD14 effect was not due to LPS contamination, since it was resistant to polymyxin and lipid IVa but ...

The role of the sympathetic nervous system in cardiac, renal and peripheral vascular adrenoceptor... more The role of the sympathetic nervous system in cardiac, renal and peripheral vascular adrenoceptor-mediated responses was investigated in patients with essential hypertension and age-matched normotensive subjects. Regardless of age, plasma adrenaline was significantly higher in hypertensive when compared with normotensive subjects. This suggests a sympatho-adrenal factor in essential hypertension. Plasma noradrenaline tended to increase with age but its similarity between normotensive and hypertensive subjects points to similar postganglionic neural activity and/or similar overflow of noradrenaline into the circulation. On the other hand, beta-adrenoceptor-mediated tachycardia in response to exercise and intravenous isoproterenol as well as the forearm vasodilator response to intraarterial isoproterenol decreased in normal subjects with older age. In hypertensives this age-dependent beta-receptor-related effect tends to be enhanced as judged from the greater reduction of cardiac isop...

Microbes and infection, Jan 6, 2017

Mycobacterium tuberculosis is one of the most successful pathogens known, having infected more th... more Mycobacterium tuberculosis is one of the most successful pathogens known, having infected more than a third of the global population. An important strategy for intracellular survival of pathogenic mycobacteria relies on their capacity to resist delivery to lysosomes, instead surviving within macrophage phagosomes. Several factors of both mycobacterial and host origin have been implicated in this process. However, whether or not this strategy is employed in vivo is not clear. Here we show that in vivo, following intravenous infection, M. tuberculosis and Mycobacterium bovis BCG initially survived by resisting lysosomal transfer. However, after prolonged infection the bacteria were transferred to lysosomes yet continued to proliferate. A M. bovis BCG mutant lacking protein kinase G (PknG), that cannot avoid lysosomal transfer and is readily cleared in vitro, was found to survive and proliferate in vivo. The ability to survive and proliferate in lysosomal organelles in vivo was found t...

J Gastrointest Surg, 2006

Macromolecular Bioscience, 2016

Thin polymer films that prevent the adhesion of bacteria are of interest as coatings for the deve... more Thin polymer films that prevent the adhesion of bacteria are of interest as coatings for the development of infection-resistant biomaterials. This study investigates the influence of grafting density and film thickness on the adhesion of Staphylococcus epidermidis to poly(poly(ethylene glycol)methacrylate) (PPEGMA) and poly(2-hydroxyethyl methacrylate) (PHEMA) brushes prepared via surface-initiated atom transfer radical polymerization (SI-ATRP). These brushes are compared with poly(ethylene glycol) (PEG) brushes, which are obtained by grafting PEG onto an epoxide-modified substrate. Except for very low grafting densities (ρ = 1%), crystal violet staining experiments show that the PHEMA and PPEGMA brushes are equally effective as the PEG-modified surfaces in preventing S. epidermis adhesion and do not reveal any significant variations as a function of film thickness or grafting density. These results indicate that brushes generated by SI-ATRP are an attractive alternative to grafted-onto PEG films for the preparation of surface coatings that resist bacterial adhesion.

Frontiers in Hypertension Research, 1981

The concept that the sympathetic nervous system might be implicated in essential hypertension was... more The concept that the sympathetic nervous system might be implicated in essential hypertension was initially founded on the antihypertensive efficacy of anti-adrenergic drugs. Direct measurement of sympathetic nerve activity is difficult in man and, therefore, indirect estimates have been sought. Plasma norepinephrine concentrations reflect the rate of norepinephrine release from postganglionic adrenergic nerve terminals (1). Only 10%–20% of norepinephrine appears in the plasma and has no appreciable effect on adrenergic receptors (2). Plasma epinephrine reflects the rate of epinephrine release from the adrenal medulla and thus splanchnic preganglionic nerve activity. Epinephrine acts as a neurohormone on postjunctional adrenergic receptors, particularly those of the beta-type; it can also be taken up by adrenergic nerve endings, thereby enhancing, via prejunctional beta-adreno-receptors, the rate of norepinephrine release (3).

Antibiotics, 2014

The number of implanted medical devices is steadily increasing and has become an effective interv... more The number of implanted medical devices is steadily increasing and has become an effective intervention improving life quality, but still carries the risk of infection. These infections are mainly caused by biofilm-forming staphylococci that are difficult to treat due to the decreased susceptibility to both antibiotics and host defense mechanisms. To understand the particular pathogenesis and treatment tolerance of implant-associated infection (IAI) animal models that closely resemble human disease are needed. Applications of the tissue cage and catheter abscess foreign body infection models in the mouse will be discussed herein. Both models allow the investigation of biofilm and virulence of various bacterial species and a comprehensive insight into the host response at the same time. They have also been proven to serve as very suitable tools to study the anti-adhesive and anti-infective efficacy of different biomaterial coatings. The tissue cage model can additionally be used to determine pharmacokinetics, efficacy and cytotoxicity of antimicrobial compounds as the tissue cage fluid can be aspirated repeatedly without the need to sacrifice the animal. Moreover, with the advance in innovative imaging systems in rodents, these models may offer new diagnostic measures of infection. In summary, animal foreign body infection models are important tools in the development of new antimicrobials against IAI and can help to elucidate the complex interactions between bacteria, the host immune system, and prosthetic materials.

Journal of leukocyte biology, 1995

In human monocytes, superoxide (O2-) generation accompanies phagocytosis and is important for bac... more In human monocytes, superoxide (O2-) generation accompanies phagocytosis and is important for bactericidal activity. It also contributes to tissue damage in inflammation. In the present study we investigated, whether lipopolysaccharide (LPS) directly stimulates monocyte O2- production with kinetics known for other LPS effects and, if so, by which mechanism. LPS caused a time- and dose-dependent O2- release in nonadherent purified monocytes. The effect appeared after 5 min, peaked at 30 min, and disappeared after 2 h. It was maximal with 10 ng/ml lipid A (+148 +/- 22%, P < .001), 1 ng/ml LPS Escherichia coli Re (+226 +/- 68%, P < .001), and 100 ng/ml LPS Salmonella abortus equi sm (+272 +/- 52%, P < .001), respectively. The effect was not observed in buffer, even when using 10 micrograms/ml LPS. It was dependent on the presence of heat-inactivated AB serum, with a maximal effect at > or = 0.5%. Serum could be replaced by LPS-binding protein (LBP). Polymyxin B and anti-LBP...

Infection and immunity, 1996

Progress in clinical and biological research, 1995

Journal of Interferon Research, 1992

ABSTRACT This study reports on biological response modification induced by prolonged continuous s... more ABSTRACT This study reports on biological response modification induced by prolonged continuous subcutaneous (s.c.) infusion of recombinant interferon-gamma (rIFN-gamma) with particular attention to changes of soluble CD14. This glycoprotein with an unknown function is derived from myeloid cells carrying membrane CD14, which is the receptor for lipopolysaccharide (LPS)-LPS-binding protein (LBP) complexes. Fifteen metastatic cancer patients received weekly escalating doses of rIFN-gamma starting at either 50 or 100 micrograms/24 h and increasing up to 400 micrograms/24 h for a median duration of 6 weeks. The maximum tolerated dose was higher (200 micrograms/24 h) with the lower (50 micrograms/24 h) starting dose. Biological activity of rIFN-gamma was evaluated by weekly measurements of CD14, neopterin, and beta 2-microglobulin concentrations in serum as well as monocyte HLA class I and II antigen expression and tumor cytotoxicity. Serum IFN-gamma concentrations increased 20-fold within 4 weeks of therapy. The levels were correlated to the mean dose (r = 0.95, p less than 0.05). Among the biological markers, two patterns were observed. First, serum CD14 concentration and expression of monocyte HLA class II antigens increased significantly during the first week, and marker expression correlated with serum IFN-gamma levels (p less than 0.05); CD14 and HLA class II antigens thereafter returned to pretreatment levels within 4 weeks of therapy despite persistently elevated serum IFN-gamma concentrations. Second, serum neopterin and beta 2-microglobulin concentrations as well as monocyte HLA class I expression also increased significantly within the first week, but remained elevated thereafter without any further dose relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Phytomedicine, 2008

The relative bioavailability of the major alkamides, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobut... more The relative bioavailability of the major alkamides, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides, from Echinacea purpurea phytotherapeutic lozenges at three different dose levels (0.07, 0.21 and 0.9 mg) was evaluated in a pharmacokinetic study in humans and the possible effects on the immunological system were measured. Alkamides were found to be rapidly absorbed and measurable in plasma 10 min after administration of 0.21 and 0.9 mg lozenges and remained detectable for 3 h for the 0.21 mg lozenges and for more then 3 h for the 0.9 mg lozenges; 0.07 mg lozenges were measurable 20 min after administration and remained detectable for only 2 h after the administration. A significant dose-independent down-regulation of the pro-inflammatory cytokines IL-12p70, IL-8, IL-6, IL-10 and TNF was observed 24 h after oral administration. The results of non-compartmental pharmacokinetic analysis revealed that a C max of (0.6570.41 ng/ml) was reached at 32 min with the 0.07 mg lozenges, (1.0070.21 ng/ml) at 25 min with the 0.21 mg lozenges and (8.8875.89 ng/ml) at 19 with the 0.9 mg lozenges. As evidenced by the doseexposure relationship, no significant departure from dose proportionality was observed, indicating linearity in pharmacokinetics. To get a further insight in pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides a compartmental population pharmacokinetic model was developed applying mixed effect modelling procedure. The results demonstrate that within the dose range studied pharmacokinetics of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamides are linear and that absorption is very rapid (t 1/2 ¼ 6 min) with apparently no lag time, thus indicating the possibility that a fraction of the drug is absorbed through the oral mucosa.

During long-term cystic fibrosis lung infections, Pseudomonas aeruginosa undergoes genetic adapta... more During long-term cystic fibrosis lung infections, Pseudomonas aeruginosa undergoes genetic adaptation resulting in progressively increased persistence and the generation of adaptive colony morphotypes. This includes small colony variants (SCVs), auto-aggregative, hyper-adherent cells whose appearance correlates with poor lung function and persistence of infection. The SCV morphotype is strongly linked to elevated levels of cyclic-di-GMP, a ubiquitous bacterial second messenger that regulates the transition between motile and sessile, cooperative lifestyles. A genetic screen in PA01 for SCVrelated loci identified the yfiBNR operon, encoding a tripartite signaling module that regulates c-di-GMP levels in P. aeruginosa. Subsequent analysis determined that YfiN is a membrane-integral diguanylate cyclase whose activity is tightly controlled by YfiR, a small periplasmic protein, and the OmpA/Pal-like outer-membrane lipoprotein YfiB. Exopolysaccharide synthesis was identified as the principal downstream target for YfiBNR, with increased production of Pel and Psl exopolysaccharides responsible for many characteristic SCV behaviors. An yfi-dependent SCV was isolated from the sputum of a CF patient. Consequently, the effect of the SCV morphology on persistence of infection was analyzed in vitro and in vivo using the YfiN-mediated SCV as a representative strain. The SCV strain exhibited strong, exopolysaccharide-dependent resistance to nematode scavenging and macrophage phagocytosis. Furthermore, the SCV strain effectively persisted over many weeks in mouse infection models, despite exhibiting a marked fitness disadvantage in vitro. Exposure to subinhibitory concentrations of antibiotics significantly decreased both the number of suppressors arising, and the relative fitness disadvantage of the SCV mutant in vitro, suggesting that the SCV persistence phenotype may play a more important role during antimicrobial chemotherapy. This study establishes YfiBNR as an important player in P. aeruginosa persistence, and implicates a central role for c-di-GMP, and by extension the SCV phenotype in chronic infections.

Journal of Neuroscience, 2005

The significance of the peripheral immune system in Alzheimer's disease pathogenesis remains cont... more The significance of the peripheral immune system in Alzheimer's disease pathogenesis remains controversial. To study the CNS invasion of hematopoietic cells in the course of cerebral amyloidosis, we used a green fluorescence protein (GFP)-bone marrow chimeric amyloid precursor protein transgenic mouse model (APP23 mice). No difference in the number of GFP-positive invading cells was observed between young APP23 mice and nontransgenic control mice. In contrast, in aged, amyloid-depositing APP23 mice, a significant increase in the number of invading ameboid-like GFP-positive cells was found compared with age-matched nontransgenic control mice. Interestingly, independent of the time after transplantation, only a subpopulation of amyloid deposits was surrounded by invading cells. This suggests that not all amyloid plaques are a target for invading cells or, alternatively, all amyloid plaques attract invading cells but only for a limited time, possibly at an early stage of plaque evolution. Immunological and ultrastructural phenotyping revealed that macrophages and T-cells accounted for a significant portion of these ameboid-like invading cells. Macrophages did not show evidence of amyloid phagocytosis at the electron microscopic level, and no obvious signs for T-cell-mediated inflammation or neurodegeneration were observed. The observation that hematopoietic cells invade the brain in response to cerebral amyloidosis may hold an unrecognized therapeutic potential.

PLoS Pathogens, 2008

Capnocytophaga canimorsus, a commensal bacterium of the canine oral flora, has been repeatedly is... more Capnocytophaga canimorsus, a commensal bacterium of the canine oral flora, has been repeatedly isolated since 1976 from severe human infections transmitted by dog bites. Here, we show that C. canimorsus exhibits robust growth when it is in direct contact with mammalian cells, including phagocytes. This property was found to be dependent on a surface-exposed sialidase allowing C. canimorsus to utilize internal aminosugars of glycan chains from host cell glycoproteins. Although sialidase probably evolved to sustain commensalism, by releasing carbohydrates from mucosal surfaces, it also contributed to bacterial persistence in a murine infection model: the wild type, but not the sialidase-deficient mutant, grew and persisted, both when infected singly or in competition. This study reveals an example of pathogenic bacteria feeding on mammalian cells, including phagocytes by deglycosylation of host glycans, and it illustrates how the adaptation of a commensal to its ecological niche in the host, here the dog's oral cavity, contributes to being a potential pathogen.