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  • 1.
    Dave, Vivek Priy
    et al.
    Technical University of Denmark, Lyngby, Denmark.
    Ngo, Tien Anh
    Technical University of Denmark, Lyngby, Denmark.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Kanit, Krishna
    Technical University of Denmark, Lyngby, Denmark.
    Nguyen, Trieu
    Technical University of Denmark, Lyngby, Denmark.
    Wolff, Anders
    Technical University of Denmark, Lyngby, Denmark.
    Bang, Dang Duong
    Technical University of Denmark, Lyngby, Denmark.
    MicroRNA amplification and detection technologies: opportunities and challenges for point of care diagnostics2018In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 99, no 4, p. 452-469Article, review/survey (Refereed)
    Abstract [en]

    The volume of point of care (POC) testing continues to grow steadily due to the increased availability of easy-to-use devices, thus making it possible to deliver less costly care closer to the patient site in a shorter time relative to the central laboratory services. A novel class of molecules called microRNAs have recently gained attention in healthcare management for their potential as biomarkers for human diseases. The increasing interest of miRNAs in clinical practice has led to an unmet need for assays that can rapidly and accurately measure miRNAs at the POC. However, the most widely used methods for analyzing miRNAs, including Northern blot-based platforms, in situ hybridization, reverse transcription qPCR, microarray, and next-generation sequencing, are still far from being used as ideal POC diagnostic tools, due to considerable time, expertize required for sample preparation, and in terms of miniaturizations making them suitable platforms for centralized labs. In this review, we highlight various existing and upcoming technologies for miRNA amplification and detection with a particular emphasis on the POC testing industries. The review summarizes different miRNA targets and signals amplification-based assays, from conventional methods to alternative technologies, such as isothermal amplification, paper-based, oligonucleotide-templated reaction, nanobead-based, electrochemical signaling-based, and microfluidic chip-based strategies. Based on critical analysis of these technologies, the possibilities and feasibilities for further development of POC testing for miRNA diagnostics are addressed and discussed.

  • 2.
    Enroth, Helena
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Retz, Karolina
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Andersson, Sofie
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Andersson, Carl
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Svensson, Kristina
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Ljungström, Lars
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Evaluation of QuickFISH and maldi Sepsityper for identification of bacteria in bloodstream infection2019In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 51, no 4, p. 249-258Article in journal (Refereed)
    Abstract [en]

    Background: Early detection of bacteria and their antibiotic susceptibility patterns are critical to guide therapeutic decision-making for optimal care of septic patients. The current gold standard, blood culturing followed by subculture on agar plates for subsequent identification, is too slow leading to excessive use of broad-spectrum antibiotic with harmful consequences for the patient and, in the long run, the public health. The aim of the present study was to assess the performance of two commercial assays, QuickFISH® (OpGen) and Maldi Sepsityper™ (Bruker Daltonics) for early and accurate identification of microorganisms directly from positive blood cultures.

    Materials and methods: During two substudies of positive blood cultures, the two commercial assays were assessed against the routine method used at the clinical microbiology laboratory, Unilabs AB, at Skaraborg Hospital, Sweden.

    Results: The Maldi Sepsityper™ assay enabled earlier microorganism identification. Using the cut-off for definite species identification according to the reference method (>2.0), sufficiently accurate species identification was achieved, but only among Gram-negative bacteria. The QuickFISH®assay was time-saving and showed high concordance with the reference method, 94.8% (95% CI 88.4–98.3), when the causative agent was covered by the QuickFISH® assay.

    Conclusions: The use of the commercial assays may shorten the time to identification of causative agents in bloodstream infections and can be a good complement to the current clinical routine diagnostics. Nevertheless, the performance of the commercial assays is considerably affected by the characteristics of the causative agents.

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  • 3.
    Helldin, Tove
    et al.
    University of Skövde, School of Informatics. University of Skövde, The Informatics Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Towards a Clinical Support System for the Early Diagnosis of Sepsis2017In: Digital Human Modeling - Applications in Health, Safety, Ergonomics, and Risk Management: Health and Safety: 8th International Conference, DHM 2017 Held as Part of HCI International 2017 Vancouver, BC, Canada, July 9–14, 2017, Proceedings, Part II / [ed] Vincent G. Duffy, Springer, 2017, p. 23-35Conference paper (Refereed)
    Abstract [en]

    Early and accurate diagnosis of sepsis is critical for patientsafety. However, this is a challenging task due to the very general symptomsassociated with sepsis, the immaturity of the tools used by theclinicians as well as the time-delays associated with the diagnostic methodsused today. This paper explores current literature regarding guidelinesfor clinical decision support, and support for sepsis diagnosis inparticular, together with guidelines extracted from interviews with fourclinicians and one biomedical analyst working at a hospital and clinicallaboratory in Sweden. The results indicate the need for the developmentof visual and interactive aids for enabling early and accurate diagnosisof sepsis.

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  • 4.
    Irani Shemirani, Mahnaz
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Göteborg Universitet.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Enroth, Helena
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Clinical Microbiology, Unilabs AB, Skövde.
    Comparison of Whole Genome Sequencing Pipelines for Analysis of Staphylococcus aureus Isolates from Sepsis Patients2019Conference paper (Refereed)
  • 5.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hornquist, Elisabeth Hultgren
    Univ Örebro, Sch Hlth & Med Sci, Dept Biomed, Örebro, Sweden.
    Toward Quantifying the Thymic Dysfunctional State in Mouse Models of Inflammatory Bowel Disease2013In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, no 4, p. 881-888Article, review/survey (Refereed)
    Abstract [en]

    Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in G alpha i2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the G alpha i2-deficient mice and in other mouse models of colitis. (Inflamm Bowel Dis 2013; 19: 881-888)

  • 6.
    Karlsson, Diana
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Ljungström, Lars
    Department of Infectious Diseases- Skaraborg Hospital, Skövde, Sweden.
    Multimarker approach for sepsis diagnostics2015In: 25th European Congress of Clinical Mircobiology and Infectious Diseases, Copenhagen, April 25-28, 2015, European Society of ClinicalMicrobiology and Infectious Diseases (ESCMID) , 2015Conference paper (Refereed)
    Abstract [en]

    OBJECTIVES

    The aim of this study was to assess the performance of a multimarker model in distinguishing patients with sepsis from those with non-infective systemic inflammatory response.

    METHODS

    This study is part of a prospective study of community-onset severe sepsis and septic shock in adults conducted from September 2011 to June 2012 at Skaraborg Hospital, in the western region of Sweden. The levels of 92 inflammation-related human protein biomarkers were measured simultaneously using Proseek® Multiplex Inflammation I96x96 (Olink Bioscience, Sweden) in 122 plasma samples collected from patients suspected with sepsis. After pre-processing normalization procedure, measurements of the markers were obtained as Normalized Protein eXpression (NPX) units on a log2 scale (GenEx, MultiD Analyses AB, Sweden). The study was approved by the Regional Ethical Review Board of Gothenburg (376-11). All patients enrolled provided written informed consent.

    To reduce the number of markers, factor analysis was performed. Thereafter, a multimarker model for classification was derived using discriminant analysis. The multimarker model consisted of a linear function of the selected markers. Cross-validation was performed by classifying each sample by the discriminant function derived from all samples other than that specific sample. The performance was assessed as area under receiving operating characteristic (ROC) curve. The cut-off for sensitivity and specificity was derived from the cut score of the discriminant function. Statistical analyses were performed in SPSS 22.0 (IBM Corporation Somers, NY USA).

    RESULTS

    Of the 122 samples, 80 (66%) were from patients diagnosed with sepsis and 42 from patients with non-infective systemic inflammatory response syndrome (SIRS). The five markers selected for the multimarker model were interleukin-6 (IL-6), cystatin D (CST5), delta and notch-like epidermal growth factor-related receptor (DNER), STAM-binding protein (STAMPB), macrophage colony-stimulating factor 1 (CSF 1). Every single marker was statistically different between the groups (p value < 0.001), except for DNER (p value 0.064) and STAMPB (p value 0.060). The area under ROC was higher for the multimarker model (81%) than for each biomarker separately (Figure 1). The accuracy for the multimarker model was 72% [64-80, 95% CI]; sensitivity 84% [77-91, 95% CI]; specificity 60% [51-69, 95% CI]; positive predictive value 79% [72-86, 95% CI]; and negative predictive value 66% [58-74, 95% CI].

    CONCLUSION

    A higher power of discrimination is obtained by combining more than one biomarker. However, the multimarker candidates identified in this study need further assessment.

  • 7.
    Kokkonen, Alexander
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Unilabs AB.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Fagerlind, Magnus
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Enroth, Helena
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Clinical Microbiology, Unilabs AB, Skövde.
    Clinical use of 16SrRNA Ion TorrentNext-generation sequencing and bioinformatics pipeline2019Conference paper (Other academic)
  • 8.
    Ljungström, Lars
    et al.
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden.
    Enroth, Helena
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Claesson, Berndt E. B.
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Ovemyr, Ida
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Karlsson, Jesper
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Fröberg, Berit
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Brodin, Anna-Karin
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Jacobsson, Gunnar
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Andersson, Rune
    Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden..
    Karlsson, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis2015In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 15, no 1, article id 199Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sepsis is a serious medical condition requiring timely administered, appropriate antibiotic therapy. Blood culture is regarded as the gold standard for aetiological diagnosis of sepsis, but it suffers from low sensitivity and long turnaround time. Thus, nucleic acid amplification tests (NAATs) have emerged to shorten the time to identification of causative microbes. The aim of the present study was to evaluate the clinical utility in everyday practice in the emergency department of two commercial NAATs in patients suspected with sepsis.

    METHODS: During a six-week period, blood samples were collected consecutively from all adult patients admitted to the general emergency department for suspicion of a community-onset sepsis and treated with intravenous antibiotics. Along with conventional blood cultures, multiplex PCR (Magicplex™) was performed on whole blood specimens whereas portions from blood culture bottles were used for analysis by microarray-based assay (Prove-it™). The aetiological significance of identified organisms was determined by two infectious disease physicians based on clinical presentation and expected pathogenicity.

    RESULTS: Among 382 episodes of suspected sepsis, clinically relevant microbes were detected by blood culture in 42 episodes (11%), by multiplex PCR in 37 episodes (9.7%), and by microarray in 32 episodes (8.4%). Although moderate agreement with blood culture (kappa 0.50), the multiplex PCR added diagnostic value by timely detection of 15 clinically relevant findings in blood culture-negative specimens. Results of the microarray corresponded very well to those of blood culture (kappa 0.90), but were available just marginally prior to blood culture results.

    CONCLUSIONS: The use of NAATs on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value by allowing for detection of organisms missed by blood culture. However, the aetiological significance of findings detected by NAATs should be interpreted with caution as the high analytical sensitivity may add findings that do not necessarily corroborate with the clinical diagnosis.

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  • 9.
    Ljungström, Lars
    et al.
    Department of Infectious Diseases, Skaraborg Hospital.
    Jacobsson, Gunnar
    Department of Infectious Diseases, Skaraborg Hospital / The swedish strategic program against antibiotic resistance.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    The diagnostic value of PCT as biomarker in patients suspected with community-onset bacterial sepsis2017Conference paper (Refereed)
  • 10.
    Ljungström, Lars
    et al.
    Skaraborg Hospital Skövde, Sweden.
    Karlsson, Diana
    Skaraborg Hospital Skövde, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Andersson, R.
    Institute of Biosciences, Sahlgrenska Academy at the University of Gothenburg, Sweden.
    Jacobsson, Gunnar
    Skaraborg Hospital Skövde, Sweden.
    Neutrophil to lymphocyte count ratio performs better than procalcitonin as a biomarker for bacteremia and severe sepsis in the emergency department2015In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 19, no Suppl 1, article id P66Article in journal (Refereed)
  • 11.
    Ljungström, Lars
    et al.
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Jacobsson, Gunnar
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden / CARe–Center for Antibiotic Resistance Research, Gothenburg University, Gothenburg, Sweden.
    Andersson, Rune
    CARe–Center for Antibiotic Resistance Research, Gothenburg University, Gothenburg, Sweden / Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Gothenburg University and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Usener, Barbara
    Department of Clinical Chemistry, Unilabs AB, Skövde, Sweden.
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e018704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Early recognition is a key factor to achieve improved outcomes for septic patients. Combinations of biomarkers, as opposed to single ones, may improve timely diagnosis and survival. We investigated the performance characteristics of sepsis biomarkers, alone and in combination, for diagnosis of verified bacterial sepsis using Sepsis-2 and Sepsis-3 criteria, respectively.

    METHODS:

    Procalcitonin (PCT), neutrophil-lymphocyte count ratio (NLCR), C-reactive protein (CRP), and lactate were determined in a total of 1,572 episodes of adult patients admitted to the emergency department on suspicion of sepsis. All sampling were performed prior to antibiotic administration. Discriminant analysis was used to construct two composite biomarkers consisting of linear combinations of the investigated biomarkers, one including three selected biomarkers (i.e., NLCR, CRP, and lactate), and another including all four (i.e., PCT, NLCR, CRP, and lactate). The diagnostic performances of the composite biomarkers as well as the individual biomarkers were compared using the area under the receiver operating characteristic curve (AUC).

    RESULTS:

    For diagnosis of bacterial sepsis based on Sepsis-3 criteria, the AUC for PCT (0.68; 95% CI 0.65-0.71) was comparable to the AUCs for the both composite biomarkers. Using the Sepsis-2 criteria for bacterial sepsis diagnosis, the AUC for the NLCR (0.68; 95% CI 0.65-0.71) but not for the other single biomarkers, was equal to the AUCs for the both composite biomarkers. For diagnosis of severe bacterial sepsis or septic shock based on the Sepsis-2 criteria, the AUCs for both composite biomarkers were significantly greater than those of the single biomarkers (0.85; 95% CI 0.82-0.88 for the composite three-biomarker, and 0.86; 95% CI 0.83-0.89 for the composite four-biomarker).

    CONCLUSIONS:

    Combinations of biomarkers can improve the diagnosis of verified bacterial sepsis in the most critically ill patients, but in less severe septic conditions either the NLCR or PCT alone exhibit equivalent performance.

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  • 12.
    Owemyr, Ida
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Enroth, Helena
    Unilabs AB, Skövde, Sweden.
    Ljungström, Lars
    Skaraborg Hospital, Skövde, Sweden.
    Jacobsson, Gunnar
    Skaraborgs Sjukhus, Skövde, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Karlsson, Diana
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Evaluation of microarray-based assay for identification of bloodstream bacteria in patients with suspected sepsis2013Conference paper (Refereed)
  • 13.
    Owemyr, Ida
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Enroth, Helena
    Unilabs AB, Skövde.
    Ljungström, Lars
    Kärnsjukhuset, Skövde.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Karlsson, Diana
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Utvärdering av microarray-baserad plattform för snabb identifiering av patogener hos patienter med misstänkt sepsis2012Conference paper (Refereed)
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  • 14.
    Pernestig, Anna-Karin
    Karolinska Institute, Stockholm.
    The study of the Escherichia coli BarA-UvrY two-component system and its ability to sense the environment.2003Doctoral thesis, comprehensive summary (Other academic)
  • 15.
    Pernestig, Anna-Karin
    et al.
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm.
    Georgellis, Dimitris
    Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México.
    Romeo, Tony
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia.
    Suzuki, Kazushi
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia.
    Tomenius, Henrik
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm.
    Normark, Staffan
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm / Swedish Institute for Infectious Disease Control, Solna, Sweden.
    The Escherichia coli BarA-UvrY two-component system is needed for efficient switching between glycolytic and gluconeogenic carbon sources2003In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 185, no 3, p. 843-853Article in journal (Refereed)
    Abstract [en]

    The Escherichia coli BarA and UvrY proteins were recently demonstrated to constitute a novel two-component system, although its function has remained largely elusive. Here we show that mutations in the sensor kinase gene, barA, or the response regulator gene, uvrY, in uropathogenic E. coli drastically affect survival in long-term competition cultures. Using media with gluconeogenic carbon sources, the mutants have a clear growth advantage when competing with the wild type, but using media with carbon sources feeding into the glycolysis leads to a clear growth advantage for the wild type. Results from competitions with mutants in the carbon storage regulation system, CsrA/B, known to be a master switch between glycolysis and gluconeogenesis, led us to propose that the BarA-UvrY two-component system controls the Csr system. Taking these results together, we propose the BarA-UvrY two-component system is crucial for efficient adaptation between different metabolic pathways, an essential function for adaptation to a new environment.

  • 16.
    Pernestig, Anna-Karin
    et al.
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Georgellis, Dimitris
    Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts.
    Identification of UvrY as the cognate response regulator for the BarA sensor kinase in Escherichia coli2001In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 1, p. 225-231Article in journal (Refereed)
    Abstract [en]

    BarA is a membrane-associated protein that belongs to a subclass of tripartite sensors of the two-component signal transduction system family. In this study, we report that UvrY is the cognate response regulator for BarA of Escherichia coli. This conclusion is based upon homologies with analogous two-component systems and demonstrated by both biochemical and genetic means. We show that the purified BarA protein is able to autophosphorylate when incubated with [gamma-(32)P]ATP but not with [alpha-(32)P]ATP or [gamma-(32)P]GTP. Phosphorylated BarA, in turn, acts as an efficient phosphoryl group donor to UvrY but not to the non-cognate response regulators ArcA, PhoB, or CpxR. The specificity of the transphosphorylation reaction is further supported by the fact that UvrY can receive the phosphoryl group from BarA-P but not from the non-cognate tripartite sensor ArcB-P or ATP. In addition, genetic evidence that BarA and UvrY mediate the same signal transduction pathway is provided by the finding that both uvrY and barA mutant strains exhibit the same hydrogen peroxide hypersensitive phenotype. These results provide the first biochemical evidence as well as genetic support for a link between BarA and UvrY, suggesting that the two proteins constitute a new two-component system for gene regulation in Escherichia coli.

  • 17.
    Pernestig, Anna-Karin
    et al.
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Normark, Staffan J.
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Georgellis, Dimitris
    Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA, USA.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    The role of the AirS two-component system in uropathogenic Escherichia coli2000In: Genes and Proteins Underlying Microbial Urinary Tract Virulence: Basic Aspects and Applications: Session II / [ed] Levente Emoődy, Tibor Pál, Jörg Hacker, Gabriele Blum-Oehler, Springer, 2000, Vol. 485, p. 137-142Conference paper (Refereed)
  • 18.
    Retz, Carolina
    et al.
    University of Skövde, The Systems Biology Research Centre.
    Andersson, Sofie
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Enroth, Helena
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Ljungström, Lars
    Department of Infectious Diseases, Skaraborg Hospital.
    Karlsson, Diana
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience.
    Pernestig, Anna-Karin
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Bioscience.
    Quicker identification of Gram-positive cocci in clusters in patients with suspected sepsis2014Conference paper (Refereed)
    Abstract [en]

    Sepsis is the primary cause of death from infection. Globally, an estimated 18 million people die from sepsis annually, exceeding deaths caused by HIV/AIDS, breast cancer, and prostate cancer combined1. Early sepsis diagnosis and targeted antimicrobial (AM) therapy reduce the length of intensive care for patients and cost by 30%2. The current gold standard, using blood cultures (BC), takes 12-72 h to detect pathogens in the blood and even longer to identify the exact pathogen and its AM susceptibility for optimal therapy. The aim of this study was to determine whether the QuickFISHTMBC test (AdvanDx, Woburn, MA) could be robust, timesaving and specific in the clinical microbiology laboratory setting, for identification of the pathogens causing life-threatening bloodstream infections.

  • 19.
    Retz, Karolina
    et al.
    Department of Clinical Microbiology, Unilabs AB, Skövde.
    Andersson, Sofie
    Department of Clinical Microbiology, Unilabs AB, Skövde .
    Andersson, Carl
    University of Skövde.
    Svensson, Kristina
    Department of Clinical Microbiology, Unilabs AB, Skövde .
    Ljungström, Lars
    The Skaraborg Hospital, Skövde, Sweden .
    Enroth, Helena
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Clinical Microbiology, Unilabs AB, Skövde .
    Tilevik, Diana
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Evaluation of the QuickFISH and the Sepsityper assays for early identification of etiological agents in bloodstream infection in a clinical routine setting2017Conference paper (Refereed)
  • 20.
    Suzuki, Kazushi
    et al.
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
    Wang, Xin
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
    Weilbacher, Thomas
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
    Pernestig, Anna-Karin
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
    Georgellis, Dimitris
    Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
    Babitzke, Paul
    Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, USA.
    Romeo, Tony
    Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
    Regulatory circuitry of the CsrA/CsrB and BarA/UvrY systems of Escherichia coli2002In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 184, no 18, p. 5130-5140Article in journal (Refereed)
    Abstract [en]

    The global regulator CsrA (carbon storage regulator) is an RNA binding protein that coordinates centralcarbon metabolism, activates flagellum biosynthesis and motility, and represses biofilm formation in Escherichiacoli. CsrA activity is antagonized by the untranslated RNA CsrB, to which it binds and forms a globularribonucleoprotein complex. CsrA indirectly activates csrB transcription, in an apparent autoregulatory mechanism.In the present study, we elucidate the intermediate regulatory circuitry of this system. Mutationsaffecting the BarA/UvrY two-component signal transduction system decreased csrB transcription but did notaffect csrA-lacZ expression. The uvrY defect was severalfold more severe than that of barA. Both csrA and uvrYwere required for optimal barA expression. The latter observation suggests an autoregulatory loop for UvrY.Ectopic expression of uvrY suppressed the csrB-lacZ expression defects caused by uvrY, csrA, or barA mutations;csrA suppressed csrA or barA defects; and barA complemented only the barA mutation. Purified UvrY proteinstimulated csrB-lacZ expression approximately sixfold in S-30 transcription-translation reactions, revealing adirect effect of UvrY on csrB transcription. Disruption of sdiA, which encodes a LuxR homologue, decreased theexpression of uvrY-lacZ and csrB-lacZ fusions but did not affect csrA-lacZ. The BarA/UvrY system activatedbiofilm formation. Ectopic expression of uvrY stimulated biofilm formation by a csrB-null mutant, indicative ofa CsrB-independent role for UvrY in biofilm development. Collectively, these results demonstrate that uvrYresides downstream from csrA in a signaling pathway for csrB and that CsrA stimulates UvrY-dependentactivation of csrB expression by BarA-dependent and -independent mechanisms.

  • 21.
    Tilevik, Diana
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Ljungström, Lars
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden.
    Clinical routine biomarkers in combination for early identification of patients with bacterial sepsis2019Conference paper (Refereed)
  • 22.
    Tilevik, Diana
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Saxenborn, Patricia
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Fagerlind, Magnus
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Lubovac-Pilav, Zelmina
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Pernestig, Anna-Karin
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Enroth, Helena
    Department of Clinical Microbiology, Unilabs AB, Skövde, Sweden.
    Using next-generation sequencing to study biodiversity in Klebsiella spp. isolated from patients with suspected sepsis2019Conference paper (Refereed)
  • 23.
    Tomenius, Henrik
    et al.
    Swedish Institute for Infectious Disease Control, SE-17182 Solna, Sweden / Microbiology and Tumorbiology Center, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences.
    Jonas, Kristina
    Swedish Institute for Infectious Disease Control, SE-17182 Solna, Sweden / Microbiology and Tumorbiology Center, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Georgellis, Dimitris
    Departamento de Genética Molecular, Instituto de Fisiologia Celular, Universidad National Autónoma de México, 04510 México D.F, Mexico.
    Möllby, Roland
    Microbiology and Tumorbiology Center, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Normark, Staffan
    Microbiology and Tumorbiology Center, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    Melefors, Öjar
    Swedish Institute for Infectious Disease Control, SE-17182 Solna, Sweden / Microbiology and Tumorbiology Center, Karolinska Institutet, SE-17177 Stockholm, Sweden.
    The Escherichia coli BarA-UvrY two-component system is a virulence determinant in the urinary tract2006In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 6, p. 27-Article in journal (Refereed)
    Abstract [en]

    Background: The Salmonella enterica BarA-SirA, the Erwinia carotovora ExpS-ExpA, the Vibrio cholerae BarA-VarA and the Pseudomonas spp GacS-GacA all belong to the same orthologous family of two-component systems as the Escherichia coli BarA-UvrY. In the first four species it has been demonstrated that disruption of this two-component system leads to a clear reduction in virulence of the bacteria. Our aim was to determine if the Escherichia coli BarA-UvrY two-component system is connected with virulence using a monkey cystitis model. Results: Cystitis was generated in Macaque fascularis monkeys by infecting the bladder with a 1: 1 mixture of the uropathogenic Escherichia coli isolate DS17 and a derivative where the uvrY gene had been disrupted with a kanamycin resistance gene. Urine was collected through bladder punctuation at subsequent time intervals and the relative amount of uvrY mutant was determined. This showed that inactivation of the UvrY response regulator leads to a reduced fitness. In similar competitions in culture flasks with Luria Broth (LB) the uvrY mutant rather had a higher fitness than the wild type. When the competitions were done in flasks with human urine the uvrY mutant initially had a lower fitness. This was followed by a fluctuation in the level of mutant in the long-term culture, with a pattern that was specific for the individual urines that were tested. Addition of LB to the different urine competition cultures however clearly led to a consistently higher fitness of the uvrY mutant. Conclusion: This paper demonstrates that the BarA-UvrY two-component system is a determinant for virulence in a monkey cystitis model. The observed competition profiles strengthen our previous hypothesis that disruption of the BarA-UvrY two-component system impairs the ability of the bacteria to switch between different carbon sources. The urine in the bladder contains several different carbon sources and its composition changes over time. Inability to efficiently switch between the carbon sources may thus provide an explanation to the reduced fitness of the uvrY mutant in the cystitis model.

  • 24.
    Tomenius, Henrik
    et al.
    Microbiology and Tumorbiology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden / Swedish Institute for Infectious Disease Control, SE-17182 Solna, Sweden.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences.
    Méndez-Catalá, Claudia F.
    Departamento de Genética Molecular, Instituto de Fisiologia Celular, Universidad National Autónoma de México, 04510 México D.F., Mexico.
    Georgellis, Dimitris
    Departamento de Genética Molecular, Instituto de Fisiologia Celular, Universidad National Autónoma de México, 04510 México D.F., Mexico.
    Normark, Staffan
    Microbiology and Tumorbiology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Melefors, Öjar
    Microbiology and Tumorbiology Center, Karolinska Institutet, SE-171 77 Stockholm, Sweden / Swedish Institute for Infectious Disease Control, SE-17182 Solna, Sweden.
    Genetic and functional characterization of the Escherichia coli BarA-UvrY two-component system: point mutations in the HAMP linker of the BarA sensor give a dominant-negative phenotype2005In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 187, no 21, p. 7317-7324Article in journal (Refereed)
    Abstract [en]

    The BarA-UvrY two-component system family is strongly associated with virulence but is poorly understood at the molecular level. During our attempts to complement a barA deletion mutant, we consistently generated various mutated BarA proteins. We reasoned that characterization of the mutants would help us to better understand the signal transduction mechanism in tripartite sensors. This was aided by the demonstrated ability to activate the UvrY regulator with acetyl phosphate independently of the BarA sensor. Many of the mutated BarA proteins had poor complementation activity but could counteract the activity of the wild-type sensor in a dominant-negative fashion. These proteins carried point mutations in or near the recently identified HAMP linker, previously implicated in signal transduction between the periplasm and cytoplasm. This created sensor proteins with an impaired kinase activity and a net dephosphorylating activity. Using further site-directed mutagenesis of a HAMP linker-mutated protein, we could demonstrate that the phosphoaccepting aspartate 718 and histidine 861 are crucial for the dephosphorylating activity. Additional analysis of the HAMP linker-mutated BarA sensors demonstrated that a dephosphorylating activity can operate via phosphotransfer within a tripartite sensor dimer in vivo. This also means that a tripartite sensor can be arranged as a dimer even in the dephosphorylating mode.

1 - 24 of 24
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