Kati Seidl
Universitätsspital Zürich, Infectious Diseases Hospital Epidemiology, Department Member
Clonality and antimicrobial susceptibility of
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There has been controversy about the intrinsic virulence of methicillin-resistant Staphylococcus aureus (MRSA) as compared to methicillin-susceptible S. aureus (MSSA). To address this discrepancy, the intrinsic virulence of 42 MRSA and 40... more
There has been controversy about the intrinsic virulence of methicillin-resistant Staphylococcus aureus (MRSA) as compared to methicillin-susceptible S. aureus (MSSA). To address this discrepancy, the intrinsic virulence of 42 MRSA and 40 MSSA clinical isolates was assessed by testing endothelial cell (EC) damage, a surrogate marker for virulence in blood stream infections. Since these clinical isolates represent a heterogeneous group, well characterized S. aureus laboratory strains with SCCmec loss- and gain-of-function mutations were used in addition. The clinical MRSA isolates carrying typical hospital acquired SCCmec types (I, II or III) induced significantly less damage (47.8%) as compared to isolates with other SCCmec types (62.3%, p=0.03) and MSSA isolates (64.2%, p<0.01). There was a strong inverse correlation between high-level oxacillin resistance and low EC damage induction (R(2)=0.4464, p<0.001). High-level oxacillin resistant strains (MIC >32μ/ml) grew signific...
Research Interests: Microbiology, Medical Microbiology, Biology, Medicine, Virulence, and 13 moreHumans, Endothelial Cells, Bacterial Toxins, Staphylococcus aureus, Gene Order, Anti-Bacterial Agents, Toxin, Methicillin Resistance, Microbial Sensitivity Tests, Host Pathogen Interactions, Medicine and Health Sciences, Cell Survival, and Methicillin Resistant Staphylococcus Aureus
BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid... more
BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid chondrosarcoma (EMC). A 54-year-old male patient developed an asymptomatic swelling of the lower leg. Imaging showed a 9.5-cm large intramuscular soft tissue mass. Due to its morphological and immunohistochemical profile on biopsy, it was initially diagnosed as an EMC. The patient was treated by complete resection and adjuvant radiotherapy and remained free of tumor at 7 years follow-up. Using next-generation sequencing (NGS), we retrospectively identified RGAG1-BCOR gene fusion (confirmed by RT-PCR), which has not been described in somatic soft tissue tumors so far. This finding broadens the spectrum of partner genes in the BCOR-rearranged sarcomas in a tumor with a well-documented, long clinical follow-up.
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BackgroundMgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA)... more
BackgroundMgrA is an important global virulence gene regulator in Staphylococcus aureus. In the present study, the role of mgrA in host-pathogen interactions related to virulence was explored in both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains.MethodsIn vitro susceptibilities to human defense peptides (HDPs), adherence to fibronectin (Fn) and endothelial cells (ECs), EC damage, α-toxin production, expression of global regulator (eg, agr RNAIII) and its downstream effectors (eg, α-toxin [hla] and Fn binding protein A [fnbA]), MgrA binding to fnbA promoter, and the effect on HDP-induced mprF and dltA expression were analyzed. The impact of mgrA on virulence was evaluated using a mouse bacteremia model.ResultsmgrA mutants displayed significantly higher susceptibility to HDPs, which might be related to the decreased HDP-induced mprF and dltA expression but decreased Fn and EC adherence, EC damage, α-toxin production, agr RNAIII, hla and fn...
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The alternative transcription factor σ B of Staphylococcus aureus affects the transcription of the cap gene cluster, required for the synthesis of capsular polysaccharide (CP), although this operon is lacking an apparent σ B -dependent... more
The alternative transcription factor σ B of Staphylococcus aureus affects the transcription of the cap gene cluster, required for the synthesis of capsular polysaccharide (CP), although this operon is lacking an apparent σ B -dependent promoter. Regulation of cap expression and CP production in S. aureus strain Newman was shown here to be influenced by σ B , the two-component signal transduction regulatory system ArlRS, and the yabJ-spoVG locus to different extents. Inactivation of arlR or deletion of the sigB operon strongly suppressed capA (CP synthesis enzyme A) transcription. Deletion of spoVG had a polar effect on yabJ-spoVG transcription and resulted in a two- to threefold decrease in capA transcription. Interestingly, immunofluorescence showed that CP production was strongly impaired in all three mutants, signaling that the yabJ-spoVG inactivation, despite its only partial effect on capA transcription, abolished capsule formation. trans -Complementation of the Δ spoVG mutant ...
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Some clinical isolates of Staphylococcus aureus produce the superantigenic toxic shock syndrome toxin 1 (TSST-1), encoded by tst, located on pathogenicity islands. The expression of tst is complex and is influenced by environmental... more
Some clinical isolates of Staphylococcus aureus produce the superantigenic toxic shock syndrome toxin 1 (TSST-1), encoded by tst, located on pathogenicity islands. The expression of tst is complex and is influenced by environmental conditions such as pH, CO2, and glucose. We identified a putative catabolite-responsive element (cre) in the promoter regions of all known tst genes, indicating that tst transcription may be regulated by the catabolite control protein CcpA. By introducing tst genes under the control of their native promoters or tst promoter-reporter gene fusions in wild-type strain Newman, we showed that glucose was able to repress tst transcription and TSST-1 production, whereas glucose repression was abolished in the corresponding ΔccpA mutant. Stabilizing the pH ruled out a pH effect due to acid production during glucose catabolism. CcpA thus directly regulates tst transcription, linking carbohydrate utilization to virulence gene expression in S. aureus.
Research Interests: Microbiology, Biology, Medicine, Western blotting, Biological Sciences, and 12 moreInfection and immunity, Glucose, Bacterial Toxins, Enterotoxins, Bacteria, Staphylococcus aureus, Medicine and Health Sciences, Virulence Factors, DNA binding proteins, Catabolite Repression, Response Elements, and Medical and Health Sciences
Background The catabolite control protein A (CcpA) is a member of the LacI/GalR family of transcriptional regulators controlling carbon-metabolism pathways in low-GC Gram-positive bacteria. It functions as a catabolite repressor or... more
Background The catabolite control protein A (CcpA) is a member of the LacI/GalR family of transcriptional regulators controlling carbon-metabolism pathways in low-GC Gram-positive bacteria. It functions as a catabolite repressor or activator, allowing the bacteria to utilize the preferred carbon source over secondary carbon sources. This study is the first CcpA-dependent transcriptome and proteome analysis in Staphylococcus aureus, focussing on short-time effects of glucose under stable pH conditions. Results The addition of glucose to exponentially growing S. aureus increased the expression of genes and enzymes of the glycolytic pathway, while genes and proteins of the tricarboxylic acid (TCA) cycle, required for the complete oxidation of glucose, were repressed via CcpA. Phosphotransacetylase and acetate kinase, converting acetyl-CoA to acetate with a concomitant substrate-level phosphorylation, were neither regulated by glucose nor by CcpA. CcpA directly repressed genes involved ...
Research Interests: Transcription Regulation, Biological Sciences, Glucose, Glucose Metabolism, Staphylococcus aureus, and 11 moreEnzyme, Gram Positive Bacteria, Carbon Metabolism, Amino Acid Profile, Proteome analysis, Amino Acid Sequence, Proteome, Carbon Source, Gene expression profiling, BMC, and Medical and Health Sciences
Carbon catabolite protein A (CcpA) is known to function as a major regulator of gene expression in different gram-positive organisms. Deletion of the ccpA homologue ( saCOL1786 ) in Staphylococcus aureus was found to affect growth,... more
Carbon catabolite protein A (CcpA) is known to function as a major regulator of gene expression in different gram-positive organisms. Deletion of the ccpA homologue ( saCOL1786 ) in Staphylococcus aureus was found to affect growth, glucose metabolization, and transcription of selected virulence determinants. In liquid culture, deletion of CcpA decreased the growth rate and yield; however, the effect was only transient during the exponential-growth phase as long as glucose was present in the medium. Depletion of glucose and production of lactate was delayed, while the level of excretion of acetate was less affected and was even higher in the mutant culture. On solid medium, in contrast, growth of the Δ ccpA mutant resulted in smaller colonies containing a lower number of CFU per colony. Deletion of CcpA had an effect on the expression of important virulence factors of S. aureus by down-regulating RNAIII , the effector molecule of the agr locus, and altering the transcription patterns...
Research Interests: Microbiology, Medical Microbiology, Biology, Medicine, Gene expression, and 15 moreAntibiotic Resistance, Glucose, Gram Positive, Staphylococcus aureus, Gram Positive Bacteria, Bacillus subtilis, Carbohydrate metabolism, DNA binding, Antimicrobial agents, DNA binding proteins, Carbon Source, Catabolite Repression, Response Elements, DNA sequence, and Pharmacology and pharmaceutical sciences
Biofilm formation in Staphylococcus aureus under in vitro growth conditions is generally promoted by high concentrations of sugar and/or salts. The addition of glucose to routinely used complex growth media triggered biofilm formation in... more
Biofilm formation in Staphylococcus aureus under in vitro growth conditions is generally promoted by high concentrations of sugar and/or salts. The addition of glucose to routinely used complex growth media triggered biofilm formation in S. aureus strain SA113. Deletion of ccpA , coding for the catabolite control protein A (CcpA), which regulates gene expression in response to the carbon source, abolished the capacity of SA113 to form a biofilm under static and flow conditions, while still allowing primary attachment to polystyrene surfaces. This suggested that CcpA mainly affects biofilm accumulation and intercellular aggregation. trans -Complementation of the mutant with the wild-type ccpA allele fully restored the biofilm formation. The biofilm produced by SA113 was susceptible to sodium metaperiodate, DNase I, and proteinase K treatment, indicating the presence of polysaccharide intercellular adhesin (PIA), protein factors, and extracellular DNA (eDNA). The investigation of seve...
Research Interests: Genetics, Microbiology, Biofilms, Biology, Medicine, and 15 moreGene expression, Biological Sciences, Infection and immunity, Biofilm, Infection, Bacteria, Staphylococcus aureus, Bacterial Adhesion, DNA binding proteins, Carbon Source, Gene expression profiling, Host Defense, foreign body, Antibiotic treatment, and Medical and Health Sciences
Endothelial cells are important in the pathogenesis of bloodstream infections caused by Candida albicans and Staphylococcus aureus. Numerous investigations have used human umbilical vein endothelial cells (HUVECs) to study... more
Endothelial cells are important in the pathogenesis of bloodstream infections caused by Candida albicans and Staphylococcus aureus. Numerous investigations have used human umbilical vein endothelial cells (HUVECs) to study microbial-endothelial cell interactions in vitro. However, the use of HUVECs requires a constant supply of umbilical cords, and there are significant donor-to-donor variations in these endothelial cells. The use of an immortalized endothelial cell line would obviate such difficulties. One candidate in this regard is HMEC-1, an immortalized human dermal microvascular endothelial cell line. To determine if HMEC-1 cells are suitable for studying the interactions of C. albicans and S. aureus with endothelial cells in vitro, we compared the interactions of these organisms with HMEC-1 cells and HUVECs. We found that wild-type C. albicans had significantly reduced adherence to and invasion of HMEC-1 cells as compared to HUVECs. Although wild-type S. aureus adhered to and...
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In the laboratory sessions of the course, we tried to isolate prokaryotes from Jori lake XIII, which is a cold, oligotrophic high mountain habitat. We were interested in finding out what kind of microorganisms could be expected to live... more
In the laboratory sessions of the course, we tried to isolate prokaryotes from Jori lake XIII, which is a cold, oligotrophic high mountain habitat. We were interested in finding out what kind of microorganisms could be expected to live under the harsh conditions there. We used molecular and physiological methods to characterize the cultures. In the end we focussed on one isolate and identified a species which had 98% similarity in the base sequence of its 16S-RNA-gene with three other species listed in the data bank: Rhizobium giardinii, Sinorhizobium sp. and an uncultured soil bacterium.
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Healthcare-associated outbreaks of vancomycin-resistant Enterococcus faecium (VREfm) are a worldwide problem with increasing prevalence. The genomic plasticity of this hospital-adapted pathogen contributes to its efficient spread despite... more
Healthcare-associated outbreaks of vancomycin-resistant Enterococcus faecium (VREfm) are a worldwide problem with increasing prevalence. The genomic plasticity of this hospital-adapted pathogen contributes to its efficient spread despite infection control measures. Here, we aimed to identify the genomic and phenotypic determinants of healthcare-associated transmission of VREfm. We assessed the VREfm transmission networks at the tertiary-care University Hospital of Zurich (USZ) between October 2014 and February 2018 and investigated microevolutionary dynamics of this pathogen. We performed whole-genome sequencing for the 69 VREfm isolates collected during this timeframe and assessed the population structure and variability of the vancomycin resistance transposon. Phylogenomic analysis allowed us to reconstruct transmission networks and to unveil external or indirect transmission networks, not detectable by traditional surveillance. Notably, it unveiled a persistent clone, sampled 31 ...
Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections are life-threatening syndromes with few therapeutic options. The potential impact of bacteriophages on the persistent outcome has not been well studied.... more
Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections are life-threatening syndromes with few therapeutic options. The potential impact of bacteriophages on the persistent outcome has not been well studied. In this study, we investigated the role of a novel prophage (ϕSA169) in MRSA persistence by using a lysogen-free clinically resolving bacteremia (RB) isolate and comparing it to a derivative which was obtained by infecting the RB strain with ϕSA169, which has been lysogenized in a clinical persistent MRSA bacteremia (PB) isolate. Similar to the PB isolate, the ϕSA169-lysogenized RB strain exhibited well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, including earlier activation of global regulators (i.e., sigB, sarA, agr RNAIII, and sae); higher expression of a critical purine biosynthesis gene, purF; and higher growth rates accompanied by lower ATP levels and vancomycin (VAN) susceptibility and ...
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Hematopoietic cell transplant (HCT) recipients are at increased risk for infections. Staphylococcus aureus (SA) colonizes 20-50% of healthy individuals and is a risk factor for subsequent invasive SA infections. Colonization rates in... more
Hematopoietic cell transplant (HCT) recipients are at increased risk for infections. Staphylococcus aureus (SA) colonizes 20-50% of healthy individuals and is a risk factor for subsequent invasive SA infections. Colonization rates in patients undergoing allogeneic HCT and clinical relevance for the time of aplasia and severely reduced immune function following HCT are not known. Only some retrospective data on methicillin-resistant SA infection rates are available. In this study, we prospectively assessed the prevalence of SA colonization in 110 consecutive patients before and during allo-HCT in a single-center observational study from June 2013 to January 2016. All patients undergoing allo-HCT were screened for nasal, pharyngeal and inguinal SA colonization weekly beginning at the time of admission to the transplant unit until neutrophil recovery. After swabs for the initial SA screening were taken all patients were put on oral gentamicin and vancomycin for gut decontamination unti...
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HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a recently described distinct tumor entity of the sinonasal tract associated with high-risk subtypes of human papilloma virus (HPV), predominantly type 33. The biological behavior... more
HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a recently described distinct tumor entity of the sinonasal tract associated with high-risk subtypes of human papilloma virus (HPV), predominantly type 33. The biological behavior seems to be less aggressive than the often high-grade, highly proliferative morphology implies; however, recurrences are frequent. Most of the cases present as polypoid tumors within the nasal cavity. Microscopic morphology frequently encompasses adenoid cystic-like features or features reminiscent of other salivary gland tumors. Here, we describe four cases of this rare entity, all observed in women. The polypoid tumors were within the nasal cavity, leading to obstruction, facial pain and epistaxis. The morphology was predominantly basaloid, solid and adenoid cystic-like in two of four cases, one with additional glomeruloid features. Another case showed basaloid tumor cells with prominent mature squamous differentiation and extensive keratinization. A single case showed a predominantly solid and reticular growth pattern. All cases were diffusely positive for p16 (100%), expressed SOX10, LEF-1 and partially S-100, and harbored HPV high-risk types 33, 56 (2×) and 82. No recurrences or metastases were detectable after 3–50 months of follow-up. Of note, three of four patients were nurses/nursing assistant. We expand the morphological spectrum by describing a glomeruloid growth pattern and extensive mature keratinization, and add HPV type 82 to the molecular spectrum. The finding of HMSC among predominantly nurses in our cohort warrants further epidemiological studies in larger cohorts.
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Staphylococcus aureus endovascular infections retain a high morbidity and mortality despite antibiotics and supportive care. The destruction of endothelial cells (ECs) is a critical step in the pathogenesis of S. aureus endovascular... more
Staphylococcus aureus endovascular infections retain a high morbidity and mortality despite antibiotics and supportive care. The destruction of endothelial cells (ECs) is a critical step in the pathogenesis of S. aureus endovascular infections. In order to better understand S. aureus-induced EC damage, we systematically screened a collection of two-component regulatory system mutants of methicillin-resistant S. aureus (MRSA) USA300 strain JE2 for damage induction in human umbilical vein ECs (HUVECs). This screen revealed that the two-component regulatory system ArlRS is required for maximum damage: arlRS inactivation leads to a > 70% reduction in damage. In a different genetic S. aureus background (RN6390, MSSA strain) arlRS inactivation had a smaller but also significant effect on EC damage. In both strains, the reduction in EC damage was accompanied by a significant reduction in internalization. In conclusion, we determined a novel role of ArlRS in S. aureus-induced EC damage, which will help to better understand the pathogenesis of S. aureus endovascular infection.
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Persistent MRSA bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared to resolving bacteremia (RB)... more
Persistent MRSA bacteremia (PB) represents an important subset of S. aureus endovascular infections. In this study, we investigated potential genetic mechanisms underlying the persistent outcomes. Compared to resolving bacteremia (RB) isolates (negative blood cultures within 2-4 days of therapy), PB strains (positive blood cultures after ≥ 7 days of therapy) had significantly: i) earlier-onset activation of key virulence regulons and structural genes (e.g., sigB, sarA, sae and cap5); ii) higher expression of purine biosynthesis genes (e.g., purF); and iii) faster growth rates, with earlier entrance into stationary phase. Importantly, an isogenic strain-set featuring a wild-type MRSA isolate, its purF-mutant and -complemented strain, and use of strategic purine biosynthesis inhibitors implicated a causal relationship between purine biosynthesis and the in vivo persistent outcomes. These observations suggest that purine biosynthesis plays a key role in the PB outcome, and may represen...
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Recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) are severely immunocompromised and are at increased risk of infection. In this prospective, observational, single-centre study including 110 allo-HSCT... more
Recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) are severely immunocompromised and are at increased risk of infection. In this prospective, observational, single-centre study including 110 allo-HSCT recipients, the rate of Staphylococcus aureus colonisation was reduced from 11.8% to 0% (P <0.001) following peritransplant oral gut decontamination. No invasive S. aureus infections were observed.
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ABSTRACTStaphylococcus aureusbiofilms are extremely difficult to treat. They provide a protected niche for the bacteria, rendering them highly recalcitrant toward host defenses as well as antibiotic treatment. Bacteria within a biofilm... more
ABSTRACTStaphylococcus aureusbiofilms are extremely difficult to treat. They provide a protected niche for the bacteria, rendering them highly recalcitrant toward host defenses as well as antibiotic treatment. Bacteria within a biofilm are shielded from the immune system by the formation of an extracellular polymeric matrix, composed of polysaccharides, extracellular DNA (eDNA), and proteins. Many antibiotics do not readily penetrate biofilms, resulting in the presence of subinhibitory concentrations of antibiotics. Here, we show that subinhibitory concentrations of clindamycin triggered a transcriptional stress response inS. aureusvia the alternative sigma factor B (σB) and upregulated the expression of the major biofilm-associated genesatlA,lrgA,agrA, thepsmgenes,fnbA, andfnbB. Our data suggest that subinhibitory concentrations of clindamycin alter the ability ofS. aureusto form biofilms and shift the composition of the biofilm matrix toward higher eDNA content. An understanding o...
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Methicillin-resistant Staphylococcus aureus (MRSA) causes community and healthcare associated infections in all age groups and treatment can be difficult due to its resistance against methicillin and other antimicrobials. The disease... more
Methicillin-resistant Staphylococcus aureus (MRSA) causes community and healthcare associated infections in all age groups and treatment can be difficult due to its resistance against methicillin and other antimicrobials. The disease spectrum ranges from superficial skin and soft tissue infections (SSTI) (1) to life-threatening invasive infections (2). Colonisation is age-dependent (3) and often precedes infection (1). Other risk factors for MRSA infections in children are not well established. We aimed to characterise paediatric MRSA infections to assess potential risk factors for transmission and infection in children in a single centre in Switzerland, a country with a very low prevalence of MRSA, at less than 1% (4). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Effect of a glucose impulse on the CcpA regulon in Staphylococcus aureus SEIDL, Kati, et al. BACKGROUND: The catabolite control protein A (CcpA) is a member of the LacI/GalR family of transcriptional regulators controlling... more
Effect of a glucose impulse on the CcpA regulon in Staphylococcus aureus SEIDL, Kati, et al. BACKGROUND: The catabolite control protein A (CcpA) is a member of the LacI/GalR family of transcriptional regulators controlling carbon-metabolism pathways in low-GC Gram-positive bacteria. It functions as a catabolite repressor or activator, allowing the bacteria to utilize the preferred carbon source over secondary carbon sources. This study is the first CcpA-dependent transcriptome and proteome analysis in Staphylococcus aureus, focussing on short-time effects of glucose under stable pH conditions. RESULTS: The addition of glucose to exponentially growing S. aureus increased the expression of genes and enzymes of the glycolytic pathway, while genes and proteins of the tricarboxylic acid (TCA) cycle, required for the complete oxidation of glucose, were repressed via CcpA. Phosphotransacetylase and acetate kinase, converting acetyl-CoA to acetate with a concomitant substrate-level phosphor...
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... 1/2 Molecular analysis of biofilm-forming bacteria from cold, oligotrophic habitats Kati Seidl,Sebastian Zurbriggen∗, Advisor: Munti Yuhana Institut für Pflanzenbiologie, Zollikerstr. 107, 8008 Zürich ... REFERENCES - Altschul,... more
... 1/2 Molecular analysis of biofilm-forming bacteria from cold, oligotrophic habitats Kati Seidl,Sebastian Zurbriggen∗, Advisor: Munti Yuhana Institut für Pflanzenbiologie, Zollikerstr. 107, 8008 Zürich ... REFERENCES - Altschul, Stephen F., Thomas L. Madden, Alejandro A. Schäffer ...
OBJECTIVE In-hospital transmission of methicillin-susceptible Staphylococcus aureus (MSSA) among neonates remains enigmatic. We describe the epidemiology of MSSA colonization and infection in a 30-bed neonatal ward. DESIGN Multimodal... more
OBJECTIVE In-hospital transmission of methicillin-susceptible Staphylococcus aureus (MSSA) among neonates remains enigmatic. We describe the epidemiology of MSSA colonization and infection in a 30-bed neonatal ward. DESIGN Multimodal outbreak investigation SETTING A public 800-bed tertiary care university hospital in Switzerland METHODS Investigations in 2012-2013, triggered by a MSSA infection cluster, included prospective MSSA infection surveillance, microbiologic screening of neonates and environment, onsite observations, and a prospective cohort study. MSSA isolates were characterized by pulsed-field gel electrophoresis (PFGE) and selected isolates were examined for multilocus sequence type (MLST) and virulence factors. RESULTS Among 726 in 2012, 30 (4.1%) patients suffered from MSSA infections including 8 (1.1%) with bacteremia. Among 655 admissions in 2013, 13 (2.0%) suffered from MSSA infections including 2 (0.3%) with bacteremia. Among 177 neonates screened for S. aureus carriage, overall 77 (44%) tested positive. A predominant PFGE-1-ST30 strain was identified in 6 of 30 infected neonates (20%) and 30 of 77 colonized neonates (39%). This persistent clone was pvl-negative, tst-positive and belonged to agr group III. We found no environmental point source. MSSA carriage was associated with central vascular catheter use but not with a particular midwife, nurse, physician, or isolette. Observed healthcare worker behavior may have propagated transmission via hands and fomites. Despite multimodal interventions, clonal transmission and colonization continued and another clone, PFGE-6-ST5, became predominant. CONCLUSIONS Hospital-acquired MSSA clones represent a high proportion of MSSA colonization but not MSSA infections in neonate inpatients. In contrast to persisting MSSA, transmission infection rates decreased concurrently with interventions. It remains to be established whether eradication of hospital-acquired MSSA strains would reduce infection rates further. Infect. Control Hosp. Epidemiol. 2015;36(11):1305-1312.
Staphylococcus aureus-infected patients treated with antibiotics that are effective in vitro often experience relapse of infection because the bacteria hide in privileged locations. These locations include abscesses and host cells, which... more
Staphylococcus aureus-infected patients treated with antibiotics that are effective in vitro often experience relapse of infection because the bacteria hide in privileged locations. These locations include abscesses and host cells, which contain low-pH compartments and are sites from which nonstable S. aureus small-colony variants (SCVs) are frequently recovered. We assessed the effect of low pH on S. aureus colony phenotype and bacterial growth, using in vitro and in vivo models of long-term infection. We showed that low pH induced nonstable SCVs and nonreplicating persisters that are capable of regrowth. Within host cells, S. aureus was located in phagolysosomes, a low-pH compartment. Therapeutic neutralization of phagolysosomal pH with ammonium chloride, bafilomycin A1, or the antimalaria drug chloroquine reduced SCVs in infected host cells. In a systemic mouse infection model, treatment with chloroquine also reduced SCVs. Our results show that the acidic environment favors formation of nonstable SCVs, which reflect the SCVs found in clinics. They also provide evidence that treatment with alkalinizing agents, together with antibiotics, may provide a novel translational strategy for eradicating persisting intracellular reservoirs of staphylococci. This approach may also be extended to other intracellular bacteria.
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The Sec pathway plays a prominent role in protein export and membrane insertion, including the secretion of major bacterial virulence determinants. The accessory Sec constituent SecDF has been proposed to contribute to protein export.... more
The Sec pathway plays a prominent role in protein export and membrane insertion, including the secretion of major bacterial virulence determinants. The accessory Sec constituent SecDF has been proposed to contribute to protein export. Deletion of Staphylococcus aureus secDF has previously been shown to reduce resistance, to alter cell separation, and to change the expression of certain virulence factors. To analyse the impact of the secDF deletion in S. aureus on protein secretion, a quantitative secretome analysis was performed. Numerous Sec signal containing proteins involved in virulence were found to be decreased in the supernatant of the secDF mutant. However, two Sec-dependent hydrolases were increased in comparison to the wild type, suggesting additional indirect, regulatory effects to occur upon deletion of secDF. Adhesion, invasion, and cytotoxicity of the secDF mutant were reduced in human umbilical vein endothelial cells. Virulence was significantly reduced using a Galler...
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Persistent MRSA infections are especially relevant to endovascular infections and correlate with suboptimal outcomes. However, the virulence signatures of Staphylococcus aureus that drive such persistence outcomes are not well defined. In... more
Persistent MRSA infections are especially relevant to endovascular infections and correlate with suboptimal outcomes. However, the virulence signatures of Staphylococcus aureus that drive such persistence outcomes are not well defined. In the current study, we investigated correlations between accessory gene regulator (agr) activation and the outcome of vancomycin treatment in an experimental model of infective endocarditis (IE) due to MRSA strains with different agr and clonal complex (CC) types. Twelve isolates with the four most common MRSA CC and agr types (CC5-agr II, CC8-agr I, CC30-agr III and CC45-agr I) were evaluated for heterogeneous vancomycin-intermediate S. aureus (hVISA), agr function, agrA and RNAIII transcription, agr locus sequences, virulence and response to vancomycin in the IE model. Early agr RNAIII activation (beginning at 2 h of growth) in parallel with strong δ-haemolysin production correlated with persistent outcomes in the IE model following vancomycin the...
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Berger-Bächi, B., Senn, MM, Ender, M., Seidl, K., Hübscher, J., Schulthess, B., Heusser, R., Stutzmann Meier, P. and McCallum, N.(2009) Resistance to β-Lactam Antibiotics, in Staphylococci in Human Disease, Second Edition (eds KB... more
Berger-Bächi, B., Senn, MM, Ender, M., Seidl, K., Hübscher, J., Schulthess, B., Heusser, R., Stutzmann Meier, P. and McCallum, N.(2009) Resistance to β-Lactam Antibiotics, in Staphylococci in Human Disease, Second Edition (eds KB Crossley, KK Jefferson, GL ...
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Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (positive blood cultures after ≥7 days) represents a challenging subset of invasive MRSA infections. The comparison of genome sequences of persistent (300-169) and... more
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (positive blood cultures after ≥7 days) represents a challenging subset of invasive MRSA infections. The comparison of genome sequences of persistent (300-169) and resolving (301-188) MRSA bacteremia isolates with similar genetic background (sequence type 45 [ST45]) will help us to better understand underlying mechanisms of persistent MRSA bacteremia.
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We established the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess damage induced by Staphylococcus aureus in human umbilical vein endothelial cells (HUVECs). The MTT assay was comparable to the... more
We established the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess damage induced by Staphylococcus aureus in human umbilical vein endothelial cells (HUVECs). The MTT assay was comparable to the previously published (51)chromium release assay. MTT reduction by intracellular S. aureus was negligible and therefore permits assessment of S. aureus induced EC damage.