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Article ; Online: The ArlRS two-component system is a regulator of Staphylococcus aureus-induced endothelial cell damage.

Seidl, Kati / Leemann, Michèle / Zinkernagel, Annelies S

European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology

2018 Volume 37, Issue 2, Page(s) 289–292

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Bacterial Proteins/genetics ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Methicillin-Resistant Staphylococcus aureus/genetics ; Methicillin-Resistant Staphylococcus aureus/pathogenicity ; Protein Kinases/genetics ; Staphylococcal Infections/microbiology ; Staphylococcal Infections/pathology ; Trans-Activators/genetics
Chemical Substances	Agr protein, Staphylococcus aureus ; ArlR protein, Staphylococcus aureus ; Bacterial Proteins ; Trans-Activators ; Protein Kinases (EC 2.7.-) ; ArlS protein, Staphylococcus aureus (EC 2.7.3.-)
Language	English
Publishing date	2018-02
Publishing country	Germany
Document type	Journal Article
ZDB-ID	603155-9
ISSN	1435-4373 ; 0934-9723 ; 0722-2211
ISSN (online)	1435-4373
ISSN	0934-9723 ; 0722-2211
DOI	10.1007/s10096-017-3130-5
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Article: Impact of the Novel Prophage ϕSA169 on Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.

Li, Liang / Wang, Genzhu / Li, Yi / Francois, Patrice / Bayer, Arnold S / Chen, Liang / Seidl, Kati / Cheung, Ambrose / Xiong, Yan Q

mSystems

2020 Volume 5, Issue 3

Abstract: Persistent methicillin- ... ...

Abstract	Persistent methicillin-resistant
Language	English
Publishing date	2020-06-30
Publishing country	United States
Document type	Journal Article
ISSN	2379-5077
ISSN	2379-5077
DOI	10.1128/mSystems.00178-20
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Article: Intracellular Environment and

Häffner, Nicola / Bär, Julian / Dengler Haunreiter, Vanina / Mairpady Shambat, Srikanth / Seidl, Kati / Crosby, Heidi A / Horswill, Alexander R / Zinkernagel, Annelies S

Frontiers in microbiology

2020 Volume 11, Page(s) 1415

Abstract: Staphylococcus ... ...

Abstract	Staphylococcus aureus
Language	English
Publishing date	2020-06-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2020.01415
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Article ; Online: Novel RGAG1-BCOR gene fusion revealed in a somatic soft tissue sarcoma with a long follow-up.

Vasella, Mauro / Wagner, Ulrich / Fritz, Christine / Seidl, Kati / Giudici, Luca / Exner, Gerhard Ulrich / Moch, Holger / Wild, Peter Johannes / Bode-Lesniewska, Beata

Virchows Archiv : an international journal of pathology

2021 Volume 480, Issue 5, Page(s) 1107–1114

Abstract: 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). ...

Abstract	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.
MeSH term(s)	Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Bone Neoplasms/pathology ; Chondrosarcoma ; Follow-Up Studies ; Gene Fusion ; Humans ; Male ; Middle Aged ; Neoplasms, Connective and Soft Tissue ; Oncogene Proteins, Fusion/genetics ; Proto-Oncogene Proteins/genetics ; Repressor Proteins/genetics ; Retrospective Studies ; Sarcoma/pathology ; Soft Tissue Neoplasms/genetics
Chemical Substances	BCOR protein, human ; Biomarkers, Tumor ; Oncogene Proteins, Fusion ; Proto-Oncogene Proteins ; Repressor Proteins
Language	English
Publishing date	2021-07-31
Publishing country	Germany
Document type	Case Reports ; Journal Article
ZDB-ID	1184867-4
ISSN	1432-2307 ; 0945-6317
ISSN (online)	1432-2307
ISSN	0945-6317
DOI	10.1007/s00428-021-03160-z
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Article ; Online: Genomic Surveillance of Vancomycin-Resistant Enterococcus faecium Reveals Spread of a Linear Plasmid Conferring a Nutrient Utilization Advantage.

Boumasmoud, Mathilde / Dengler Haunreiter, Vanina / Schweizer, Tiziano A / Meyer, Lilly / Chakrakodi, Bhavya / Schreiber, Peter W / Seidl, Kati / Kühnert, Denise / Kouyos, Roger D / Zinkernagel, Annelies S

mBio

2022 Volume 13, Issue 2, Page(s) e0377121

Abstract: 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 ... ...

Abstract	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 health care-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 time frame 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 wider transmission networks undetectable by routine surveillance. Notably, it unveiled a
MeSH term(s)	Enterococcus faecium/genetics ; Genomics ; Gram-Positive Bacterial Infections/microbiology ; Humans ; Nutrients ; Plasmids/genetics ; Vancomycin/pharmacology ; Vancomycin-Resistant Enterococci/genetics
Chemical Substances	Vancomycin (6Q205EH1VU)
Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.03771-21
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Article ; Online: The MTT assay is a rapid and reliable quantitative method to assess Staphylococcus aureus induced endothelial cell damage.

Seidl, Kati / Zinkernagel, Annelies S

Journal of microbiological methods

2013 Volume 92, Issue 3, Page(s) 307–309

Abstract: 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) ...

Abstract	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.
MeSH term(s)	Cell Survival ; Cells, Cultured ; Chromium Radioisotopes/metabolism ; Cytological Techniques/methods ; Endothelial Cells/microbiology ; Endothelial Cells/physiology ; Humans ; Staining and Labeling/methods ; Staphylococcus aureus/pathogenicity ; Tetrazolium Salts/metabolism ; Thiazoles/metabolism
Chemical Substances	Chromium Radioisotopes ; Tetrazolium Salts ; Thiazoles ; thiazolyl blue (EUY85H477I)
Language	English
Publishing date	2013-03
Publishing country	Netherlands
Document type	Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604916-3
ISSN	1872-8359 ; 0167-7012
ISSN (online)	1872-8359
ISSN	0167-7012
DOI	10.1016/j.mimet.2012.12.018
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Article ; Online: MgrA Governs Adherence, Host Cell Interaction, and Virulence in a Murine Model of Bacteremia Due to Staphylococcus aureus.

Li, Liang / Wang, Genzhu / Cheung, Ambrose / Abdelhady, Wessam / Seidl, Kati / Xiong, Yan Q

The Journal of infectious diseases

2019 Volume 220, Issue 6, Page(s) 1019–1028

Abstract: Background: MgrA 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 ... ...

Abstract	Background: MgrA 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. Methods: In 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. Results: mgrA 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 fnbA expression, and attenuated virulence in the bacteremia model as compared to their respective parental and mgrA-complemented strains. Importantly, direct binding of MgrA to the fnbA promoter was observed. Conclusions: These results suggest that mgrA mediates host-pathogen interactions and virulence and may provide a novel therapeutic target for invasive S. aureus infections.
MeSH term(s)	Adhesins, Bacterial/metabolism ; Aminoacyltransferases/metabolism ; Animals ; Bacteremia/microbiology ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Toxins/metabolism ; Cell Communication/physiology ; Disease Models, Animal ; Endothelial Cells/metabolism ; Female ; Fibronectins ; Gene Deletion ; Gene Expression Regulation, Bacterial ; Hemolysin Proteins/metabolism ; Host-Pathogen Interactions ; Humans ; Methicillin-Resistant Staphylococcus aureus ; Mice ; RNA, Bacterial/metabolism ; Staphylococcal Infections/metabolism ; Staphylococcal Infections/microbiology ; Staphylococcus aureus/genetics ; Staphylococcus aureus/metabolism ; Staphylococcus aureus/pathogenicity ; Virulence/genetics ; Virulence Factors/genetics
Chemical Substances	Adhesins, Bacterial ; Bacterial Proteins ; Bacterial Toxins ; Fibronectins ; Hemolysin Proteins ; RNA, Bacterial ; RNAIII, Staphylococcus aureus ; Virulence Factors ; fibronectin-binding proteins, bacterial ; staphylococcal alpha-toxin ; Aminoacyltransferases (EC 2.3.2.-) ; mprF protein, Staphylococcus aureus (EC 2.3.2.-)
Language	English
Publishing date	2019-05-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiz219
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Article ; Online: Single-cell resolved ploidy and chromosomal aberrations in nonalcoholic steatohepatitis-(NASH) induced hepatocellular carcinoma and its precursor lesions.

Friemel, Juliane / Torres, Irianna / Brauneis, Elizabeth / Thörner, Tim / Schäffer, Alejandro A / Gertz, E Michael / Grob, Tobias / Seidl, Kati / Weber, Achim / Ried, Thomas / Heselmeyer-Haddad, Kerstin

Scientific reports

2022 Volume 12, Issue 1, Page(s) 22622

Abstract: Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to widespread obesity. We assessed copy number changes of genes associated with ... ...

Abstract	Nonalcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC) and its precursor, nonalcoholic fatty liver disease (NAFLD) are an unmet health issue due to widespread obesity. We assessed copy number changes of genes associated with hepatocarcinogenesis and oxidative pathways at a single-cell level. Eleven patients with NASH-HCC and 11 patients with NAFLD were included. Eight probes were analyzed using multiplex interphase fluorescence in situ hybridization (miFISH), single-cell imaging and phylogenetic tree modelling: Telomerase reverse transcriptase (TERT), C-Myc (MYC), hepatocyte growth factor receptor tyrosine kinase (MET), tumor protein 53 (TP53), cyclin D1 (CCND1), human epidermal growth factor receptor 2 (HER2), the fragile histidine triad gene (FHIT) and FRA16D oxidoreductase (WWOX). Each NASH-HCC tumor had up to 14 distinct clonal signal patterns indicating multiclonality, which correlated with high tumor grade. Changes frequently observed were TP53 losses, 45%; MYC gains, 36%; WWOX losses, 36%; and HER2 gains, 18%. Whole-genome duplications were frequent (82%) with aberrant tetraploid cells evolving from diploid ancestors. Non-tumorous NAFLD/NASH biopsies did not harbor clonal copy number changes. Fine mapping of NASH-HCC using single-cell multiplex FISH shows that branched tumor evolution involves genome duplication and that multiclonality increases with tumor grade. The loss of oxidoreductase WWOX and HER2 gains could be potentially associated with NASH-induced hepatocellular carcinoma.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/pathology ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/pathology ; Liver Neoplasms/pathology ; In Situ Hybridization, Fluorescence ; Phylogeny ; Chromosome Aberrations ; Neoplasm Proteins/genetics ; Ploidies ; Oxidoreductases/genetics
Chemical Substances	Neoplasm Proteins ; Oxidoreductases (EC 1.-)
Language	English
Publishing date	2022-12-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-27173-z
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Article ; Online: HPV-Related Multiphenotypic Sinonasal Carcinoma: Four Cases that Expand the Morpho-Molecular Spectrum and Include Occupational Data.

Rupp, Niels J / Camenisch, Ulrike / Seidl, Kati / Rushing, Elisabeth J / Anderegg, Nanina / Broglie, Martina A / Holzmann, David / Morand, Grégoire B

Head and neck pathology

2019 Volume 14, Issue 3, Page(s) 623–629

Abstract: 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 ...

Abstract	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.
MeSH term(s)	Aged ; Carcinoma/pathology ; Carcinoma/virology ; Female ; Humans ; Middle Aged ; Nose Neoplasms/pathology ; Nose Neoplasms/virology ; Nurses ; Papillomaviridae ; Papillomavirus Infections/complications
Language	English
Publishing date	2019-09-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2407834-7
ISSN	1936-0568 ; 1936-055X
ISSN (online)	1936-0568
ISSN	1936-055X
DOI	10.1007/s12105-019-01079-1
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Article ; Online: Modulation of Staphylococcus aureus Biofilm Matrix by Subinhibitory Concentrations of Clindamycin.

Schilcher, Katrin / Andreoni, Federica / Dengler Haunreiter, Vanina / Seidl, Kati / Hasse, Barbara / Zinkernagel, Annelies S

Antimicrobial agents and chemotherapy

2016 Volume 60, Issue 10, Page(s) 5957–5967

Abstract: Staphylococcus aureus biofilms 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 ... ...

Abstract	Staphylococcus aureus biofilms 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 in S. aureus via the alternative sigma factor B (σ(B)) and upregulated the expression of the major biofilm-associated genes atlA, lrgA, agrA, the psm genes, fnbA, and fnbB Our data suggest that subinhibitory concentrations of clindamycin alter the ability of S. aureus to form biofilms and shift the composition of the biofilm matrix toward higher eDNA content. An understanding of the molecular mechanisms underlying biofilm assembly and dispersal in response to subinhibitory concentrations of clinically relevant antibiotics such as clindamycin is critical to further optimize antibiotic treatment strategies of biofilm-associated S. aureus infections.
MeSH term(s)	Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/pharmacology ; Biofilms/drug effects ; Clindamycin/administration & dosage ; Clindamycin/pharmacology ; Dose-Response Relationship, Drug ; Extracellular Matrix/drug effects ; Extracellular Matrix/genetics ; Gene Expression Regulation, Bacterial/drug effects ; Humans ; Mutation ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/isolation & purification ; Staphylococcus aureus/physiology
Chemical Substances	Anti-Bacterial Agents ; Clindamycin (3U02EL437C)
Language	English
Publishing date	2016-09-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00463-16
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