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  • 51. Nilsson, Carol L
    et al.
    Cooper, Helen J
    Håkansson, Kristina
    Marshall, Alan G
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lavrinovicha, Marija
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Characterization of the P13 membrane protein of Borrelia burgdorferi by mass spectrometry.2002In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 13, no 4, p. 295-299Article in journal (Refereed)
    Abstract [en]

    Borrelia burgdorferi sensu lato is a tick-borne pathogen that causes Lyme disease. The characterization of membrane proteins from this and other pathogens may yield a better understanding of the mechanisms of infection and information useful for vaccine design. Characterization of the highly hydrophobic Borrelia outer membrane component P13 from a mutant (OspA- OspB- OspC- and OspD-) strain was undertaken by use of a combination of mass spectrometric methods. In a previous investigation, an electrospray ionization (ESI) mass spectrum of the intact protein provided an average molecular weight that was 20 Da lower than the predicted molecular weight. The mass deviation could be explained by a modification of the N-terminus of the protein such as pyroglutamylation (-17 Da) in combination with the experimental error of measurement, however more information was required. New structural information for this membrane protein was provided by peptide mapping with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) and sequencing with ESI-quadrupole-TOF tandem MS.

  • 52.
    Noppa, Laila
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lavrinovicha, Marija
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    P13, an integral membrane protein of Borrelia burgdorferi, is C-terminally processed and contains surface-exposed domains2001In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 69, no 5, p. 3323-3334Article in journal (Refereed)
    Abstract [en]

    To elucidate antigens present on the bacterial surface of Borrelia burgdorferi sensu lato that may be involved in pathogenesis, we characterized a protein, P13, with an apparent molecular mass of 13 kDa. The protein was immunogenic and was expressed in large amounts during in vitro cultivation compared to other known antigens. An immunofluorescence assay, immunoelectron microscopy, and protease sensitivity assays indicated that P13 is surface exposed. The deduced sequence of the P13 peptide revealed a possible signal peptidase type I cleavage site, and computer analysis predicted that P13 is an integral membrane protein with three transmembrane-spanning domains. Mass spectrometry, in vitro translation, and N- and C-terminal amino acid sequencing analyses indicated that P13 was posttranslationally processed at both ends and modified by an unknown mechanism. Furthermore, p13 belongs to a gene family with five additional members in B. burgdorferi sensu stricto. The p13 gene is located on the linear chromosome of the bacterium, in contrast to five paralogous genes, which are located on extrachromosomal plasmids. The size of the p13 transcript was consistent with a monocistronic transcript. This new gene family may be involved in functions that are specific for this spirochete and its pathogenesis.

  • 53. Nordstrand, Annika
    et al.
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Larsson, Christer
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Tsogbe, Kodjo
    Schwan, Tom G
    Nilsson, Mikael
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Tickborne relapsing fever diagnosis obscured by malaria, Togo.2007In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 13, no 1, p. 117-123Article in journal (Refereed)
    Abstract [en]

    Given the prevalence of relapsing fever (RF) in Senegal, this disease may cause illness and death in other areas of West Africa. We performed a cross-sectional, clinic-based study to investigate the presence of RF in Togo during 2002-2004. Blood samples from patients with fever were examined for RF spirochetes by microscopy, PCR, and DNA sequencing of amplicons and for antibodies to the glycerophosphodiester phosphodiesterase antigen. Although no spirochetes were seen in blood smears, approximately 10% of the patients were positive by PCR and approximately 13% were seropositive for spirochetes. DNA sequencing demonstrated that Borrelia crocidurae and B. duttonii were present. Most patients were treated for malaria whether or not plasmodia were observed. Thus, many RF patients originally had a misdiagnosis of malaria, which resulted in ineffective treatment. The inability of microscopic analysis to detect spirochetes compared with PCR demonstrates the need for tests with greater sensitivity.

  • 54.
    Normark, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nelson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Björk, Rafael
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Moritz, Thomas
    Umeå Plant Science Centre (UPSC), Swedish University of Agricultural Sciences (SLU), Umeå, Sweden.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e103295Article in journal (Refereed)
    Abstract [en]

    In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1 beta and TNF-alpha, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.

  • 55. Orikiiriza, Judy
    et al.
    Surowiec, Izabella
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindquist, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bonde, Mari
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lipid response patterns in acute phase paediatric Plasmodium falciparum malaria2017In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, no 4, article id 41Article in journal (Refereed)
    Abstract [en]

    Introduction: Several studies have observed serum lipid changes during malaria infection in humans. All of them were focused at analysis of lipoproteins, not specific lipid molecules. The aim of our study was to identify novel patterns of lipid species in malaria infected patients using lipidomics profiling, to enhance diagnosis of malaria and to evaluate biochemical pathways activated during parasite infection.

    Methods: Using a multivariate characterization approach, 60 samples were representatively selected, 20 from each category (mild, severe and controls) of the 690 study participants between age of 0.5–6 years. Lipids from patient’s plasma were extracted with chloroform/methanol mixture and subjected to lipid profiling with application of the LCMS-QTOF method.

    Results: We observed a structured plasma lipid response among the malaria-infected patients as compared to healthy controls, demonstrated by higher levels of a majority of plasma lipids with the exception of even-chain length lysophosphatidylcholines and triglycerides with lower mass and higher saturation of the fatty acid chains. An inverse lipid profile relationship was observed when plasma lipids were correlated to parasitaemia.

    Conclusions: This study demonstrates how mapping the full physiological lipid response in plasma from malaria-infected individuals can be used to understand biochemical processes during infection. It also gives insights to how the levels of these molecules relate to acute immune responses.

  • 56. Ornstein, Katharina
    et al.
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bunikis, Jonas
    Noppa, Laila
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berglund, Johan
    Norrby, Ragnar
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Differential immune response to the variable surface loop antigen of P66 of Borrelia burgdorferi sensu lato species in geographically diverse populations of lyme borreliosis patients2002In: Clinical and diagnostic laboratory immunology, ISSN 1071-412X, Vol. 9, no 6, p. 1382-1384Article in journal (Refereed)
    Abstract [en]

    We have studied the immune response to a variable surface-exposed loop region of the P66 outer membrane protein from Borrelia burgdorferi sensu lato by using an enzyme immunoassay. Lyme borreliosis populations found in North America and Sweden were preferentially more seroreactive to P66 from their respective regional species, namely, B. burgdorferi sensu stricto and B. garinii and B. afzelii, respectively.

  • 57. Ovchinnikova, Olga
    et al.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Bailey, Leslie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Rudling, Mats
    Jung, Christian
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hansson, Göran K
    Nordström, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice--brief report.2009In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 29, no 10, p. 1478-1480Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Osteoprotegerin (OPG) is a tumor necrosis factor receptor-related cytokine, initially found to inhibit osteoclastogenesis. In the present study we investigated the effect of OPG treatment on atherosclerosis. METHODS AND RESULTS: Hypercholesterolemic apoe(-/-) mice were treated with recombinant 15 mg/kg OPG or vehicle injections twice a week for 10 consecutive weeks. Mice treated with OPG showed increased amounts of smooth muscle cells and collagen within the atherosclerotic lesions. OPG treatment did not affect atherosclerotic lesion size (8.2% versus 7.6%) or total vessel area but led to a 250% increase in lesion collagen, formation of mature collagen fibers in subendothelial fibrous caps, and upregulated mRNA for lysyl oxidase that promotes collagen crosslinking. In cell culture studies, OPG promoted cell proliferation in rat aortic smooth muscle cells. In contrast, OPG treatment did not affect markers of vascular or systemic inflammation. CONCLUSIONS: OPG treatment promotes smooth muscle accumulation, collagen fiber formation, and development of fibrous caps but does not affect inflammatory properties of atherosclerotic lesions. Its effects may contribute to plaque stabilization.

  • 58.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Aspán, A.
    Department of Bacteriology, National Veterinary Institute, SE-750 07 Uppsala, Sweden.
    Bengtsson, K.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Blomquist, L.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wollin, R.
    Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Salmonella carriage in European Black headed gulls (Larus ridibundus) in SwedenManuscript (preprint) (Other academic)
  • 59.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Aspán, Anna
    SVA.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bengtsson, Kennet
    Blomquist, Lennart
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wollin, Ralf
    SVA.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Salmonella in Black-headed gulls ( Larus ridibundus); prevalence, genotypes and influence on Salmonella epidemiology.2006In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 134, no 3, p. 635-644Article in journal (Refereed)
    Abstract [en]

    During a period of 3 years, 1998-2000, 1047 faecal swabs from Black-headed gulls were sampled at one location in Southern Sweden. Salmonella spp. was found in 28 individuals (2.7%) and the dominating serotype found was S. Typhimurium (83%). Twenty-five per cent of the Salmonella-infected gulls were later recaptured and re-sampled. We found that Salmonella infection in Black-headed gulls was of short duration, and that infection in this bird species was predominantly expressed as carriage without disease manifestations. All S. Typhimurium isolates were subjected to antibiotic resistance profiling and molecular characterization by pulsed-field gel electrophoresis and IS200 polymerase chain reaction. The S. Typhimurium gull isolates were compared to human and domestic animal isolates of the same serotype and phage type. We found genetic relatedness of S. Typhimurium DT195 isolates from gulls, domestic animals and humans, indicating that Black-headed gulls might play a role in the spread of S. Typhimurium in Sweden.

  • 60.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    McCafferty, D.
    British Antarctic SurŠey, National EnŠironment Research Council, Cambridge, UK.
    Aspán, A.
    Department of Bacteriology, National Veterinary Institute, Uppsala, Sweden.
    Broman, Tina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Wollin, R.
    Department of Bacteriology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Department of Infectious Diseases, Kalmar County Hospital, S-381 95 Kalmar, Sweden.
    Salmonella in sub-Antarctica: low heterogeneity in salmonella serotypes in South Georgian seals and birds2000In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 125, no 2, p. 257-262Article in journal (Refereed)
    Abstract [en]

    The number of human visitors to Antarctica is increasing rapidly, and with it a risk of introducing infectious organisms to native animals. To study the occurrence of salmonella serotypes in sub- Antarctic wildlife, faecal samples were collected from gentoo penguins, macaroni penguins, gray-headed albatrosses, black-browed albatrosses and Antarctic fur seals on Bird Island in the South Georgian archipelago during the austral summer of 1996 and 1998. In 1996, S. havana, S. typhimurium and S. enteritidis were isolated from 7% of gentoo penguins and 4% of fur seals. In 1998, however, 22% of fur seals were found to be infected with S. havana, S. enteritidis and S. newport. All isolates, except one, showed identical pulsed-field gel electrophoresis-patterns within each serotype, irrespective of sampling year and animal reservoir. No significant antibiotic resistance was found. The very low heterogeneity in the salmonella isolates found could either indicate a high genetic adaptation of the bacteria to the environment or a recent introduction of salmonella into the area.

  • 61.
    Palmgren, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Olsen, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Enteropathogenic Bacteria in Migrating Birds Arriving in Sweden1997In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 29, no 6, p. 565-568Article in journal (Refereed)
    Abstract [en]

    Birds have been thought to play a role in transmitting infectious agents like influenza, Borrelia and Salmonella. To investigate the role of migrating birds in the dispersal of enteropathogenic bacteria, stool samples from 151 wild birds (50 gulls and 101 passerines) just entering Sweden from their winter grounds were analysed for Salmonella spp., Campylobacter spp. and EHEC O157:H7. The thermophilic isolated enteropathogens found were further analysed by antibiograms. Among the 50 gulls examined, we found 2 isolates of Salmonella typhimurium with multiple antibiotic resistance. Three isolates of C. jejuni were found in the 101 stool samples from passerines. We did not isolate EHEC O157:H7 in any of the bird stools examined.

  • 62. Pettersson, Fredrik
    et al.
    Vogt, Anna M
    Jonsson, Cathrine
    Mok, Bobo W
    Shamaei-Tousi, Alireza
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Chen, Qijun
    Wahlgren, Mats
    Whole-body imaging of sequestration of Plasmodium falciparum in the rat.2005In: Infect Immun, ISSN 0019-9567, Vol. 73, no 11, p. 7736-46Article in journal (Refereed)
    Abstract [en]

    The occlusion of vessels by packed Plasmodium falciparum-infected (iRBC) and uninfected erythrocytes is a characteristic postmortem finding in the microvasculature of patients with severe malaria. Here we have employed immunocompetent Sprague-Dawley rats to establish sequestration in vivo. Human iRBC cultivated in vitro and purified in a single step over a magnet were labeled with 99mtechnetium, injected into the tail vein of the rat, and monitored dynamically for adhesion in the microvasculature using whole-body imaging or imaging of the lungs subsequent to surgical removal. iRBC of different lines and clones sequester avidly in vivo while uninfected erythrocytes did not. Histological examination revealed that a multiadhesive parasite adhered in the larger microvasculature, inducing extensive intravascular changes while CD36- and chondroitin sulfate A-specific parasites predominantly sequester in capillaries, inducing no or minor pathology. Removal of the adhesive ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), preincubation of the iRBC with sera to PfEMP1 or preincubation with soluble PfEMP1-receptors prior to injection significantly reduced the sequestration. The specificity of iRBC binding to the heterologous murine receptors was confirmed in vitro, using primary rat lung endothelial cells and rat lung cryosections. In offering flow dynamics, nonmanipulated endothelial cells, and an intact immune system, we believe this syngeneic animal model to be an important complement to existing in vitro systems for the screening of vaccines and adjunct therapies aiming at the prevention and treatment of severe malaria.

  • 63.
    Pinne, Marija
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Takade, Akemi
    Mizunoe, Yoshimitsu
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Structural characterization of Borrelia burgdorferi porins by electron crystallographyManuscript (Other academic)
  • 64.
    Pinne, Marija
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Denker, Katrin
    Nilsson, Elin
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    The BBA01 protein, a member of paralog family 48 from Borrelia burgdorferi, is potentially interchangeable with the channel-forming protein P13.2006In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 188, no 12, p. 4207-4217Article in journal (Refereed)
    Abstract [en]

    The Borrelia burgdorferi genome exhibits redundancy, with many plasmid-carried genes belonging to paralogous gene families. It has been suggested that certain paralogs may be necessary in various environments and that they are differentially expressed in response to different conditions. The chromosomally located p13 gene which codes for a channel-forming protein belongs to paralog family 48, which consists of eight additional genes. Of the paralogous genes from family 48, the BBA01 gene has the highest homology to p13. Herein, we have inactivated the BBA01 gene in B. burgdorferi strain B31-A. This mutant shows no apparent phenotypic difference compared to the wild type. However, analysis of BBA01 in a C-terminal protease A (CtpA)-deficient background revealed that like P13, BBA01 is posttranslationally processed at its C terminus. Elevated BBA01 expression was obtained in strains with the BBA01 gene introduced on the shuttle vector compared to the wild-type strain. We could further demonstrate that BBA01 is a channel-forming protein with properties surprisingly similar to those of P13. The single-channel conductance, of about 3.5 nS, formed by BBA01 is comparable to that of P13, which together with the high degree of sequence similarity suggests that the two proteins may have similar and interchangeable functions. This is further strengthened by the up-regulation of the BBA01 protein and its possible localization in the outer membrane in a p13 knockout strain, thus suggesting that P13 can be replaced by BBA01.

  • 65.
    Pinne, Marija
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Thein, Marcus
    Denker, Katrin
    Benz, Roland
    Coburn, Jenifer
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Elimination of chanel-forming activity by insertional inactivation of the p66 gene in Borrelia burgdorferi.2007In: FEMS Microbiol Lett, Vol. 266, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Abstract P66 is a chromosomally encoded 66-kDa integral outer membrane protein of the Lyme disease agent Borrelia burgdorferi exhibiting channel-forming activity. Herein, we inactivated and subsequently complemented the p66 gene in the B31-A (WT) strain. The P66 protein was also inactivated in two other channel-forming protein mutant strains, P13-18 (Deltap13) and Deltabba01, and then compared with the channel-forming activities of wild-type and various p66 mutant strains. We further investigated the ion-selectivity of native, purified P66. In conclusion, we show that the porin activity of P66 is eliminated by insertional inactivation and that this activity can be rescued by gene complementation.

  • 66.
    Pinne, Marija
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Comstedt, Pär
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Molecular analysis of the channel-forming protein P13 and its paralogue family 48 from different Lyme disease Borrelia species2004In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 150, no Pt 3, p. 549-559Article in journal (Refereed)
    Abstract [en]

    The aetiological agent of Lyme disease, Borrelia burgdorferi cycles between its tick vector and mammalian hosts, implying that it can sense different environments and consequently change the expression of genes encoding several surface-associated proteins. The genome of the type strain B. burgdorferi B31 has revealed 175 different gene families. The p13 gene, situated on the chromosome, encodes a channel-forming protein that belongs to the gene family 48 consisting of eight additional paralogous genes. The heterogeneity of the P13 protein from different Lyme disease Borrelia strains was investigated. The predicted surface-exposed domains are the most heterogeneous regions and contain probable epitopes of P13. The membrane-spanning architecture of P13 was determined and a model for the location of this protein in the outer membrane is presented. The transcription of the paralogues of gene family 48 during in vitro culturing and in a mouse infection model was also analysed. The bba01 gene is the only p13 paralogue present in all three Lyme-disease-causing genospecies; it is stable during cultivation in vitro and the BBA01 protein was expressed in all Borrelia strains investigated. Conversely, paralogues bbi31, bbq06 and bbh41 were only detected in B. burgdorferi and the corresponding plasmids harbouring bbi31 and bbh41 were lost during in vitro passage. Finally, p13 and bbi31 are the only members of gene family 48 that are transcribed in mice, suggesting their importance during mammalian infection.

  • 67. Reuterswärd, Philippa
    et al.
    Bergström, Sofia
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Svahn, Helene Andersson
    Ayoglu, Burcu
    Uhlén, Mathias
    Wahlgren, Mats
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ribacke, Ulf
    Nilsson, Peter
    Levels of human proteins in plasma associated with acute paediatric malaria2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 426Article in journal (Refereed)
    Abstract [en]

    Background: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts.

    Results: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10−14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria.

    Conclusion: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.

  • 68. Ristow, Laura
    et al.
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lin, Yi-Pin
    Sato, Hiromi
    Curtis, Michael
    Wesley, Erin
    Hahn, Beth
    Fang, Juan
    Wilcox, David
    Leong, John
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Coburn, Jenifer
    Integrin binding by Borrelia burgdorferi P66 facilitates dissemination but is not required for infectivity2015In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 17, no 7, p. 1021-1036Article in journal (Refereed)
    Abstract [en]

    P66, a Borrelia burgdorferi surface protein with porin and integrin-binding activities, is essential for murine infection. The role of P66 integrin-binding activity in B. burgdorferi infection was investigated and found to affect transendothelial migration. The role of integrin binding, specifically, was tested by mutation of two amino acids (D205A,D207A) or deletion of seven amino acids (Del202–208). Neither change affected surface localization or channel-forming activity of P66, but both significantly reduced binding to αvβ3. Integrin-binding deficient B. burgdorferi strains caused disseminated infection in mice at 4 weeks post-subcutaneous inoculation, but bacterial burdens were significantly reduced in some tissues. Following intravenous inoculation, the Del202–208 bacteria were below the limit of detection in all tissues assessed at 2 weeks post-inoculation, but bacterial burdens recovered to wild-type levels at 4 weeks post-inoculation. The delay in tissue colonization correlated with reduced migration of the Del202–208 strains across microvascular endothelial cells, similar to Δp66bacteria. These results indicate that integrin binding by P66 is important to efficient dissemination of B. burgdorferi, which is critical to its ability to cause disease manifestations in incidental hosts and to its maintenance in the enzootic cycle.

  • 69. Sandholm, Kerstin
    et al.
    Henningsson, Anna J.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ernerudh, Jan
    Ekdahl, Kristina Nilsson
    Complement activation and phagocytosis in vitro of two strains of Borrelia burgdorferi S.L2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1153-1153Article in journal (Other academic)
  • 70.
    Sandholm, Kerstin
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Henningsson, Anna J.
    Ryhov Cty Hosp, Dept Clin Microbiol, Jonkoping, Sweden.
    Save, Susanne
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Pia
    Linkoping Univ, Dept Infect Med, Linkoping, Sweden.
    Jonsson, Nina
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Ernerudh, Jan
    Linkoping Univ, Dept Clin Immunol & Transfus Med, Linkoping, Sweden.
    Ekdahl, Kristina N.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.
    Early cytokine release in response to live Borrelia burgdorferi sensu lato spirochetes is largely complement independent2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108013-Article in journal (Refereed)
    Abstract [en]

    Aim: Here we investigated the role of complement activation in phagocytosis and the release of cytokines and chemokines in response to two clinical isolates: Borrelia afzelii K78, which is resistant to complement-mediated lysis, and Borrelia garinii LU59, which is complement-sensitive.

    Methods: Borrelia spirochetes were incubated in hirudin plasma, or hirudin-anticoagulated whole blood. Complement activation was measured as the generation of C3a and sC5b-9. Binding of the complement components C3, factor H, C4, and C4BP to the bacterial surfaces was analyzed. The importance of complement activation on phagocytosis, and on the release of cytokines and chemokines, was investigated using inhibitors acting at different levels of the complement cascade.

    Results: 1) Borrelia garinii LU59 induced significantly higher complement activation than did Borrelia afzelii K78. 2) Borrelia afzelii K78 recruited higher amounts of factor H resulting in significantly lower C3 binding. 3) Both Borrelia strains were efficiently phagocytized by granulocytes and monocytes, with substantial inhibition by complement blockade at the levels of C3 and C5. 4) The release of the pro-inflammatory cytokines and chemokines IL-1 beta, IL-6, TNF, CCL20, and CXCL8, together with the anti-inflammatory IL-10, were increased the most (by>10-fold after exposure to Borrelia). 5) Both strains induced a similar release of cytokines and chemokines, which in contrast to the phagocytosis, was almost totally unaffected by complement blockade.

    Conclusions: Our results show that complement activation plays an important role in the process of phagocytosis but not in the subsequent cytokine release in response to live Borrelia spirochetes.

  • 71. Schueler, Wolfgang
    et al.
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Weber-Lehman, Jacqueline
    Comstedt, Paer
    Kutschan-Bunikis, Sabrina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Stanek, Gerold
    Huber, Jutta
    Meinke, Andreas
    Bergstrom, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundberg, Urban
    Complete Genome Sequence of Borrelia afzelii K78 and Comparative Genome Analysis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3Article in journal (Refereed)
    Abstract [en]

    The main Borrelia species causing Lyme borreliosis in Europe and Asia are Borrelia afzelii, B. garinii, B. burgdorferi and B. bavariensis. This is in contrast to the United States, where infections are exclusively caused by B. burgdorferi. Until to date the genome sequences of four B. afzelii strains, of which only two include the numerous plasmids, are available. In order to further assess the genetic diversity of B. afzelii, the most common species in Europe, responsible for the large variety of clinical manifestations of Lyme borreliosis, we have determined the full genome sequence of the B. afzelii strain K78, a clinical isolate from Austria. The K78 genome contains a linear chromosome (905,949 bp) and 13 plasmids (8 linear and 5 circular) together presenting 1,309 open reading frames of which 496 are located on plasmids. With the exception of lp28-8, all linear replicons in their full length including their telomeres have been sequenced. The comparison with the genomes of the four other B. afzelii strains, ACA-1, PKo, HLJ01 and Tom3107, as well as the one of B. burgdorferi strain B31, confirmed a high degree of conservation within the linear chromosome of B. afzelii, whereas plasmid encoded genes showed a much larger diversity. Since some plasmids present in B. burgdorferi are missing in the B. afzelii genomes, the corresponding virulence factors of B. burgdorferi are found in B. afzelii on other unrelated plasmids. In addition, we have identified a species specific region in the circular plasmid, cp26, which could be used for species determination. Different non-coding RNAs have been located on the B. afzelii K78 genome, which have not previously been annotated in any of the published Borrelia genomes.

  • 72.
    Sellstedt, Magnus
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nyberg, Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rosenbaum, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Engström, Patrik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wickström, Malin
    Department of Medicinal Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Gullbo, Joachim
    Department of Medicinal Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Lennart B-Å
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold2010In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 32, p. 6171-6178Article in journal (Refereed)
    Abstract [en]

    A series of compounds based on a novel fluorescent scaffold have been synthesized. Most of the compounds displayed high quantum yields of fluorescence and unusually long fluorescence lifetimes. HeLa cells were treated with one of the compounds and its use as a fluorescent dye was demonstrated with fluorescence confocal microscopy.

  • 73. Sjöwall, J
    et al.
    Carlsson, A
    Vaarala, O
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ernerudh, J
    Forsberg, P
    Ekerfelt, C
    Innate immune responses in Lyme borreliosis: enhanced tumour necrosis factor-alpha and interleukin-12 in asymptomatic individuals in response to live spirochetes2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 1, p. 89-98Article in journal (Refereed)
    Abstract [en]

    Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in DCs and IL-1 beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.

  • 74. Sjöwall, Johanna
    et al.
    Fryland, Linda
    Nordberg, Marika
    Sjögren, Florence
    Garpmo, Ulf
    Jansson, Christian
    Carlsson, Sten-Anders
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ernerudh, Jan
    Nyman, Dag
    Forsberg, Pia
    Ekerfelt, Christina
    Decreased Th1-type inflammatory cytokine expression in the skin is associated with persisting symptoms after treatment of erythema migrans2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18220-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the good prognosis of erythema migrans (EM), some patients have persisting symptoms of various character and duration post-treatment. Several factors may affect the clinical outcome of EM, e.g. the early interaction between Borrelia (B.) burgdorferi and the host immune response, the B. burgdorferi genotype, antibiotic treatment as well as other clinical circumstances. Our study was designed to determine whether early cytokine expression in the skin and in peripheral blood in patients with EM is associated with the clinical outcome.

    METHODS: A prospective follow-up study of 109 patients with EM was conducted at the Åland Islands, Finland. Symptoms were evaluated at 3, 6, 12 and 24 months post-treatment. Skin biopsies from the EM and healthy skin were immunohistochemically analysed for expression of interleukin (IL)-4, IL-10, IL-12p70 and interferon (IFN)-γ, as well as for B. burgdorferi DNA. Blood samples were analysed for B. burgdorferi antibodies, allergic predisposition and levels of systemic cytokines.

    FINDINGS: None of the patients developed late manifestations of Lyme borreliosis. However, at the 6-month follow-up, 7 of 88 patients reported persisting symptoms of diverse character. Compared to asymptomatic patients, these 7 patients showed decreased expression of the Th1-associated cytokine IFN-γ in the EM biopsies (p=0.003). B. afzelii DNA was found in 48%, B. garinii in 15% and B. burgdorferi sensu stricto in 1% of the EM biopsies, and species distribution was the same in patients with and without post-treatment symptoms. The two groups did not differ regarding baseline patient characteristics, B. burgdorferi antibodies, allergic predisposition or systemic cytokine levels.

    CONCLUSION: Patients with persisting symptoms following an EM show a decreased Th1-type inflammatory response in infected skin early during the infection, which might reflect a dysregulation of the early immune response. This finding supports the importance of an early, local Th1-type response for optimal resolution of LB.

  • 75.
    Skogman, Barbro H.
    et al.
    Department of Pediatrics, Falun General Hospital, Falun, Sweden.
    Hellberg, Sandra
    Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ekerfelt, Christina
    Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jenmalm, Maria C.
    Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Forsberg, Pia
    Division of Infectious Diseases, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ludvigsson, Johnny
    Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ernerudh, Jan
    Division of Clinical Immunology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed Asymptomatic children and children with Previous Clinical Lyme Borreliosis2012In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, Vol. 2012, p. 294587-294597Article in journal (Refereed)
    Abstract [en]

    Why some individuals develop clinical manifestations in Lyme borreliosis (LB) while others remain asymptomatic is largely unknown. Therefore, we wanted to investigate adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed Borrelia-antibody-positive asymptomatic children (n = 20), children with previous clinical LB (n = 24), and controls (n = 20). Blood samples were analyzed for Borrelia-specific interferon (IFN)-gamma, interleukin (IL)-4, and IL-17 secretion by ELISPOT and Borrelia-induced IL-1 beta, IL-6, IL-10, IL-12(p70), and tumor necrosis factor (TNF) secretion by Luminex. We found no significant differences in cytokine secretion between groups, but a tendency towards an increased spontaneous secretion of IL-6 was found among children with previous clinical LB. In conclusion, the adaptive or innate immune responsiveness to Borrelia burgdorferi sensu lato was similar in Borrelia-exposed asymptomatic children and children with previous clinical LB. Thus, the immunological mechanisms of importance for eradicating the spirochete effectively without developing clinical manifestations of LB remain unknown.

  • 76. Steptoe, A
    et al.
    Gylfe, Åsa
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Shamaei-Tousi, A
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Henderson, B
    Pathogen burden and cortisol profiles over the day2009In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 137, no 12, p. 1816-1824Article in journal (Refereed)
    Abstract [en]

    Hypothalamic-pituitary-adrenocortical (HPA) regulation in adults is influenced by early psychosocial adversity, but the role of infectious disease history is poorly understood. We studied the association between cumulative pathogen burden and cortisol profile over the day in a sample of 317 healthy men and women aged 51-72 years. Cumulative pathogen burden was defined as positive serostatus for Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV-1). Salivary cortisol was sampled repeatedly over the day. The cortisol slope was defined as the decrease across the day and evening. Age, gender, grade of employment, body mass index, smoking status, self-rated health, cardiovascular medication, depressed mood and time of waking were included as covariates. The pathogen burden averaged 1.76 (S.D. = 0.92). The cortisol slope was inversely associated with pathogen burden after controlling for covariates. When individual pathogens were studied, only CMV was associated with flatter cortisol rhythms in isolation. We conclude that pathogen burden is independently associated with flatter cortisol slopes over the day, and may contribute to disturbed neuroendocrine regulation.

  • 77. Steptoe, A
    et al.
    Shamaei-Tousi, A
    Gylfe, A
    Henderson, B
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Marmot, M
    Socioeconomic status, pathogen burden and cardiovascular disease risk.2007In: Heart, ISSN 1468-201X, Vol. 93, no 12, p. 1567-70Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Socioeconomic status (SES) is inversely associated with coronary heart disease (CHD) risk. Cumulative pathogen burden may also predict future CHD. The hypothesis was tested that lower SES is associated with a greater pathogen burden, and that pathogen burden accounts in part for SES differences in cardiovascular risk factors. METHODS: This was a cross-sectional observational study involving the clinical examination of 451 men and women aged 51-72 without CHD, recruited from the Whitehall II epidemiological cohort. SES was defined by grade of employment, and pathogen burden by summing positive serostatus for Chlamydia pneumoniae, cytomegalovirus and herpes simplex virus 1. Cardiovascular risk factors were also assessed. RESULTS: Pathogen burden averaged 1.94 (SD) 0.93 in the lower grade group, compared with 1.64 (0.97) and 1.64 (0.93) in the intermediate and higher grade groups (p = 0.011). Pathogen burden was associated with a higher body mass index, waist/hip ratio, blood pressure and incidence of diabetes. There were SES differences in waist/hip ratio, high-density lipoprotein-cholesterol, fasting glucose, glycated haemoglobin, lung function, smoking and diabetes. The SES gradient in these cardiovascular risk factors was unchanged when pathogen burden was taken into account statistically. CONCLUSIONS: Although serological signs of infection with common pathogens are more frequent in lower SES groups, their distribution across the social gradient does not match the linear increases in CHD risk present across higher, intermediate and lower SES groups. Additionally, pathogen burden does not appear to mediate SES differences in cardiovascular risk profiles.

  • 78. Steptoe, Andrew
    et al.
    Shamaei-Tousi, Alireza
    Gylfte, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bailey, Leslie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Coates, Anthony
    Henderson, Brian
    Protective effect of human heat shock protein 60 suggested by its association with decreased seropositivity to pathogens.2007In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 14, no 2Article in journal (Other (popular science, discussion, etc.))
  • 79.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 358Article in journal (Refereed)
    Abstract [en]

    Background: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.

    Methods: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA (R)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).

    Results: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.

    Conclusions: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

  • 80.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Erik
    Stenlund, Hans
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Umeå, Sweden.
    Quantification of run order effect on chromatography: mass spectrometry profiling data2018In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, p. 229-234Article in journal (Refereed)
    Abstract [en]

    Chromatographic systems coupled with mass spectrometry detection are widely used in biological studies investigating how levels of biomolecules respond to different internal and external stimuli. Such changes are normally expected to be of low magnitude and therefore all experimental factors that can influence the analysis need to be understood and minimized. Run order effect is commonly observed and constitutes a major challenge in chromatography-mass spectrometry based profiling studies that needs to be addressed before the biological evaluation of measured data is made. So far there is no established consensus, metric or method that quickly estimates the size of this effect. In this paper we demonstrate how orthogonal projections to latent structures (OPLS®) can be used for objective quantification of the run order effect in profiling studies. The quantification metric is expressed as the amount of variation in the experimental data that is correlated to the run order. One of the primary advantages with this approach is that it provides a fast way of quantifying run-order effect for all detected features, not only internal standards. Results obtained from quantification of run order effect as provided by the OPLS can be used in the evaluation of data normalization, support the optimization of analytical protocols and identification of compounds highly influenced by instrumental drift. The application of OPLS for quantification of run order is demonstrated on experimental data from plasma profiling performed on three analytical platforms: GCMS metabolomics, LCMS metabolomics and LCMS lipidomics.

  • 81.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Karlsson, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nelson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kyamanwa, Patrick
    Karenzi, Ben
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. nfectious Diseases Institute, School of Medicine and Health Sciences, Makerere University, Uganda.
    Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria2015In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 2, no 2Article in journal (Refereed)
    Abstract [en]

    Background: Accuracy in malaria diagnosis and staging is vital in order to reduce mortality and post infectious sequelae. Herein we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods: A group of 421 patients between six months and six years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192 and 122 individuals respectively. A multivariate design was used as basis for representative selection of twenty patients in each category. Patient plasma was subjected to Gas Chromatography-Mass Spectrometry analysis and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in-vivo model where metabolic profiles were discernible over time of infection. Results: A two-component principal component analysis (PCA) revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, two sub-groups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusion: Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

  • 82.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Skotare, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjögren, Rickard
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Gouveia-Figueira, Sandra C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy Tatwan
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Joint and unique multiblock analysis of biological data: multiomics malaria study2019In: Faraday discussions (Online), ISSN 1359-6640, E-ISSN 1364-5498Article in journal (Refereed)
    Abstract [en]

    Modern profiling technologies enable obtaining large amounts of data which can be later used for comprehensive understanding of the studied system. Proper evaluation of such data is challenging, and cannot be faced by bare analysis of separate datasets. Integrated approaches are necessary, because only data integration allows finding correlation trends common for all studied data sets and revealing hidden structures not known a priori. This improves understanding and interpretation of the complex systems. Joint and Unique MultiBlock Analysis (JUMBA) is an analysis method based on the OnPLS-algorithm that decomposes a set of matrices into joint parts containing variation shared with other connected matrices and variation that is unique for each single matrix. Mapping unique variation is important from a data integration perspective, since it certainly cannot be expected that all variation co-varies. In this work we used JUMBA for integrated analysis of lipidomic, metabolomic and oxylipin datasets obtained from profiling of plasma samples from children infected with P. falciparum malaria. P. falciparum is one of the primary contributors to childhood mortality and obstetric complications in the developing world, what makes development of the new diagnostic and prognostic tools, as well as better understanding of the disease, of utmost importance. In presented work JUMBA made it possible to detect already known trends related to disease progression, but also to discover new structures in the data connected to food intake and personal differences in metabolism. By separating the variation in each data set into joint and unique, JUMBA reduced complexity of the analysis, facilitated detection of samples and variables corresponding to specific structures across multiple datasets and by doing this enabled fast interpretation of the studied system. All this makes JUMBA a perfect choice for multiblock analysis of systems biology data.

  • 83. Talagrand-Reboul, Emilie
    et al.
    Boyer, Pierre H.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vial, Laurence
    Boulanger, Nathalie
    Relapsing Fevers: Neglected Tick-Borne Diseases2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 98Article, review/survey (Refereed)
    Abstract [en]

    Relapsing fever still remains a neglected disease and little is known on its reservoir, tick vector and physiopathology in the vertebrate host. The disease occurs in temperate as well as tropical countries. Relapsing fever borreliae are spirochaetes, members of the Borreliaceae family which also contain Lyme disease spirochaetes. They are mainly transmitted by Ornithodoros soft ticks, but some species are vectored by ixodid ticks. Traditionally a Borrelia species is associated with a specific vector in a particular geographical area. However, new species are regularly described, and taxonomical uncertainties deserve further investigations to better understand Borrelia vector/host adaptation. The medical importance of Borrelia miyamotoi, transmitted by Ixodes spp., has recently spawned new interest in this bacterial group. In this review, recent data on tick-host-pathogen interactions for tick-borne relapsing fevers is presented, with special focus on B. miyamotoi.

  • 84. Thein, Marcus
    et al.
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Denker, Katrin
    Sickmann, Albert
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    DipA, a Pore-Forming Protein in the Outer Membrane of Lyme Disease Spirochetes Exhibits Specificity for the Permeation of Dicarboxylates2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36523-Article in journal (Refereed)
    Abstract [en]

    Lyme disease Borreliae are highly dependent on the uptake of nutrients provided by their hosts. Our study describes the identification of a 36 kDa protein that functions as putative dicarboxylate-specific porin in the outer membrane of Lyme disease Borrelia. The protein was purified by hydroxyapatite chromatography from Borrelia burgdorferi B31 and designated as DipA, for dicarboxylate-specific porin A. DipA was partially sequenced, and corresponding genes were identified in the genomes of B. burgdorferi B31, Borrelia garinii PBi and Borrelia afzelii PKo. DipA exhibits high homology to the Oms38 porins of relapsing fever Borreliae. B. burgdorferi DipA was characterized using the black lipid bilayer assay. The protein has a single-channel conductance of 50 pS in 1 M KCl, is slightly selective for anions with a permeability ratio for cations over anions of 0.57 in KCl and is not voltage-dependent. The channel could be partly blocked by different di- and tricarboxylic anions. Particular high stability constants up to about 28,000 l/mol (in 0.1 M KCl) were obtained among the 11 tested anions for oxaloacetate, 2-oxoglutarate and citrate. The results imply that DipA forms a porin specific for dicarboxylates which may play an important role for the uptake of specific nutrients in different Borrelia species.

  • 85. Thein, Marcus
    et al.
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Denker, Katrin
    Larsson, Christer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cutler, Sally
    Drancourt, Michel
    Schwan, Tom G
    Mentele, Reinhard
    Lottspeich, Friedrich
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Oms38 is the first identified pore-forming protein in the outer membrane of relapsing fever spirochetes2008In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 190, no 21, p. 7035-7042Article in journal (Refereed)
    Abstract [en]

    Relapsing fever is a worldwide, endemic disease caused by several spirochetal species belonging to the genus Borrelia. During the recurring fever peaks, borreliae proliferate remarkably quickly compared to the slow dissemination of Lyme disease Borrelia and therefore require efficient nutrient uptake from the blood of their hosts. This study describes the identification and characterization of the first relapsing fever porin, which is present in the outer membranes of B. duttonii, B. hermsii, B. recurrentis, and B. turicatae. The pore-forming protein was purified by hydroxyapatite chromatography and designated Oms38, for outer membrane-spanning protein of 38 kDa. Biophysical characterization of Oms38 was done by using the black lipid bilayer method, demonstrating that Oms38 forms small, water-filled channels of 80 pS in 1 M KCl that did not exhibit voltage-dependent closure. The Oms38 channel is slightly selective for anions and shows a ratio of permeability for cations over anions of 0.41 in KCl. Analysis of the deduced amino acid sequences demonstrated that Oms38 contains an N-terminal signal sequence which is processed under in vivo conditions. Oms38 is highly conserved within the four studied relapsing fever species, sharing an overall amino acid identity of 58% and with a strong indication for the presence of amphipathic beta-sheets.

  • 86. Toledo-Arana, A
    et al.
    Anda, P
    Escudero, R
    Larsson, Christer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benach, JL
    Phylogenetic analysis of a virulent Borrelia species isolated from patients with relapsing fever2010In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 48, no 7, p. 2484-2489Article in journal (Refereed)
    Abstract [en]

    Multilocus sequence analysis (MLSA) was used to clarify the taxonomic status of a virulent Borrelia organism previously isolated from patients with relapsing fever and from ticks in Spain that is designated the Spanish relapsing fever (SRF) Borrelia. This species has been used extensively in experimental infection models because of its continued virulence. Seven genes were amplified to analyze the phylogenetic relationships among several Spanish isolates of SRF Borrelia and other relapsing fever Borrelia species. The genes targeted in this study included rrs and flaB, which have commonly been used in phylogenetic studies; the rrf-rrl intergenic spacer (IGS), which is highly discriminatory; and four additional genes, p66, groEL, glpQ, and recC, which are located on the chromosome and which have therefore evolved in a clonal way. The species included in this study were Borrelia duttonii, B. recurrentis, B. crocidurae, and B. hispanica as Old World Borrelia species and B. turicatae and B. hermsii as New World Borrelia species. The results obtained by MLSA of the SRF Borrelia on the basis of 1% of the genomic sequence data analyzed confirmed that the SRF Borrelia isolates are B. hispanica. However, the prototype isolates of B. hispanica used in this study have an uncertain history and display unique phenotypic characteristics that are not shared with the SRF Borrelia. Therefore, we propose to use strain SP1, isolated from a relapsing fever patient in 1994 in southern Spain, as the type strain for B. hispanica.

  • 87. Waldenström, Jonas
    et al.
    Lundkvist, Ake
    Falk, Kerstin I
    Garpmo, Ulf
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindegren, Gunnel
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Mejlon, Hans
    Fransson, Thord
    Haemig, Paul D
    Olsen, Björn
    Migrating birds and tickborne encephalitis virus2007In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 13, no 8, p. 1215-8Article in journal (Refereed)
    Abstract [en]

    During spring and autumn 2001, we screened 13,260 migrating birds at Ottenby Bird Observatory, Sweden, and found 3.4% were infested with ticks. Four birds, each a different passerine species, carried tickborne encephalitis virus (TBEV)-infected ticks (Ixodes ricinus). Migrating birds may play a role in the geographic dispersal of TBEV-infected ticks.

  • 88. Widhe, M
    et al.
    Ekerfelt, C
    Jarefors, S
    Skogman, B H
    Peterson, E M
    Bergström, S
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, P
    Ernerudh, J
    T-cell epitope mapping of the Borrelia garinii outer surface protein A in lyme neuroborreliosis.2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 70, no 2, p. 141-8Article in journal (Refereed)
    Abstract [en]

    We studied the T-cell reactivity to overlapping peptides of B. garinii OspA, in order to locate possible immunodominant T-cell epitopes in neuroborreliosis. Cells from cerebrospinal fluid (CSF) and blood from 39 patients with neuroborreliosis and 31 controls were stimulated with 31 overlapping peptides, and interferon-gamma secreting cells were detected by ELISPOT. The peptides OspA(17-36), OspA(49-68), OspA(105-124), OspA(137-156), OspA(193-212) and OspA(233-252) showed the highest frequency of positive responses, being positive in CSF from 38% to 50% of patients with neuroborreliosis. These peptides also elicited higher responses in CSF compared with controls (P = 0.004). CSF cells more often showed positive responses to these peptides than blood cells (P = 0.001), in line with a compartmentalization to the central nervous system. Thus, a set of potential T-cell epitopes were identified in CSF cells from patients with neuroborreliosis. Further studies may reveal whether these epitopes can be used diagnostically and studies involving HLA interactions may show their possible pathogenetic importance.

  • 89. Widhe, Mona
    et al.
    Jarefors, Sara
    Ekerfelt, Christina
    Vrethem, Magnus
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Forsberg, Pia
    Ernerudh, Jan
    Borrelia-specific interferon-gamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: association with clinical outcome.2004In: J Infect Dis, ISSN 0022-1899, Vol. 189, no 10, p. 1881-91Article in journal (Refereed)
    Abstract [en]

    The Borrelia-specific interferon (IFN)- gamma and interleukin (IL)-4 responses of 113 patients and control subjects were analyzed using the sensitive enzyme-linked immunospot method. Cerebrospinal fluid (CSF) and blood samples were obtained, during the course of disease, from patients with chronic or nonchronic neuroborreliosis (NB) and from control subjects without NB. Blood samples were obtained from patients with Lyme skin manifestations and from healthy blood donors. Early increased secretion of Borrelia-specific IFN- gamma (P<.05) and subsequent up-regulation of IL-4 (P<.05) were detected in the CSF cells of patients with nonchronic NB. In contrast, persistent Borrelia-specific IFN- gamma responses were observed in the CSF cells of patients with chronic NB (P<.05). In patients with erythema migrans, increased IFN- gamma (P<.001) was observed in blood samples obtained early during the course of disease, whereas increased IL-4 (P<.05) was observed after clearance. On the contrary, patients with acrodermatitis chronica atrophicans had Borrelia-specific IFN- gamma (P<.001), but not IL-4, detected in blood samples. The present data suggest that an initial IFN- gamma response, followed by up-regulation of IL-4, is associated with nonchronic manifestations, whereas a persistent IFN- gamma response may lead to chronic Lyme borreliosis.

  • 90. Widhe, Mona
    et al.
    Skogman, Barbro Hedin
    Jarefors, Sara
    Eknefelt, Mattias
    Eneström, Gunilla
    Nordwall, Maria
    Ekerfelt, Christina
    Croner, Stefan
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Forsberg, Pia
    Ernerudh, Jan
    Up-regulation of Borrelia-specific IL-4- and IFN-gamma-secreting cells in cerebrospinal fluid from children with Lyme neuroborreliosis.2005In: Int Immunol, ISSN 0953-8178, Vol. 17, no 10, p. 1283-91Article in journal (Refereed)
    Abstract [en]

    The Lyme disease-pathogen Borrelia burgdorferi binds the complement inhibitor factor H (FH) to its outer surface protein E- (OspE) and BbA68-families of lipoproteins. In earlier studies, only serum-resistant strains of the genospecies B. burgdorferi sensu stricto or B. afzelii, but not serum-sensitive B. garinii strains, have been shown to bind FH. Since B. garinii often causes neuroborreliosis in man, we have readdressed the interactions of B. garinii with FH. B. garinii 50/97 strain did not express FH-binding proteins. By transforming the B. garinii 50/97 strain with an OspE-encoding gene from complement-resistant B. burgdorferi (ospE-297), its resistance to serum killing could be increased. OspE genes were detected and cloned from the B. garinii BITS, Pistoia and 40/97 strains by PCR and sequencing. The deduced amino acid sequences differed in an N-terminal lysine-rich FH-binding region from OspE sequences of resistant strains. Recombinant B. garinii BITS OspE protein was found to have a considerably lower FH-binding activity than the B. burgdorferi sensu stricto 297 OspE protein P21 (P21-297). Unlike bacteria that had been kept in culture for a long time, neurovirulent B. garinii strains from neuroborreliosis patients were found to express approximately 27-kDa FH-binding proteins. These were not recognized by polyclonal anti-OspE or anti-BbA68 antibodies. We conclude that B. garinii strains carry ospE genes but have a decreased expression of OspE proteins and a reduced ability to bind FH, especially when grown for prolonged periods in vitro. Recently isolated neuroinvasive B. garinii strains, however, can express FH-binding proteins, which may contribute to the virulence of neuroborreliosis-causing B. garinii strains.

  • 91. Wilhelmsson, Peter
    et al.
    Fryland, Linda
    Börjesson, Stefan
    Nordgren, Johan
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ernerudh, Jan
    Forsberg, Pia
    Lindgren, Per-Eric
    Prevalence and diversity of Borrelia species in ticks that have bitten humans in Sweden2010In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 48, no 11, p. 4169-4176Article in journal (Refereed)
    Abstract [en]

    Members of the genus Borrelia are among the most common infectious agents causing tick-borne disease in humans worldwide. Here, we developed a Light Upon eXtension (LUX) real-time PCR assay that can detect and quantify Borrelia species in ticks that have fed on humans, and we applied the assay to 399 such ticks. Borrelia PCR-positive ticks were identified to species level by sequencing the products of conventional PCR performed using Borrelia group-specific primers. There was a 19% prevalence of Borrelia spp. in the detached ticks, and the number of spirochetes per Borrelia PCR-positive tick ranged from 2.0 x 10(2) to 4.9 x 10(5), with a median of 7.8 x 10(3) spirochetes. Adult ticks had a significantly larger number of spirochetes, with a median of 8.4 x 10(3) compared to the median of nymphs of 4.4 x 10(3). [corrected] Adult ticks also exhibited a higher prevalence of Borrelia (33%) than nymphs (14%). Among the identified species, Borrelia afzelii was found to predominate (61%) and was followed by B. garinii (23%), B. valaisiana (13%), B. burgdorferi sensu stricto (1%), B. lusitaniae (1%), and B. miyamotoi-like (1%). Also, 3% of the ticks were coinfected with multiple strains of B. afzelii. Notably, this is the first report of B. lusitaniae being detected in ticks in Sweden. Our LUX real-time PCR assay proved to be more sensitive than a corresponding TaqMan assay. In conclusion, the novel LUX real-time PCR method is a rapid and sensitive tool for detection and quantification of Borrelia spp. in ticks.

  • 92.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Berg, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Comstedt, Pär
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wieslander, Åke
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Functional analysis of a lipid galactosyltransferase synthesizing the major envelope lipid in the Lyme disease spirochete Borrelia burgdorferi2007In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 272, no 1, p. 22-29Article in journal (Refereed)
    Abstract [en]

    One of the major lipids in the membranes of Borrelia burgdorferi is monogalactosyl diacylglycerol (MGalDAG), a glycolipid recently shown to carry antigenic potency. Herein, it is shown that the gene mgs (TIGR designation bb0454) of B. burgdorferi encodes for the protein bbMGS that, when expressed in Escherichia coli, catalyzes the glycosylation of 1,2-diacylglycerol with specificity for the donor substrate UDP-Gal yielding MGalDAG. Related lipid enzymes were found in many Gram-positive bacteria. The presence of this galactosyltransferase activity and synthesis of a cholesteryl galactoside by another enzyme were verified in B. burgdorferi cell extract. Besides MGalDAG, phosphatidylcholine, phosphatidylglycerol, and cholesterol were also found as major lipids in the cell envelope. The high isoelectric point of bbMGS and clustered basic residues in its amino acid sequence suggest that the enzyme interacts with acidic lipids in the plasma membrane, in agreement with strong enzymatic activation of bbMGS by phosphatidylglycerol. The membrane packing and immunological properties of MGalDAG are likely to be of great importance in vivo.

  • 93.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bunikis, Ignas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The etiological agent of Lyme disease, Borrelia burgdorferi, appears to contain2004In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 186, no 24, p. 8472-8477Article in journal (Refereed)
    Abstract [en]

    Small regulatory RNAs (sRNAs) have recently been shown to be the main controllers of several regulatory pathways. The function of sRNAs depends in many cases on the RNA-binding protein Hfq, especially for sRNAs with an antisense function. In this study, the genome of Borrelia burgdorferi was subjected to different searches for sRNAs, including direct homology and comparative genomics searches and ortholog- and annotation-based search strategies. Two new sRNAs were found, one of which showed complementarity to the rpoS region, which it possibly controls by an antisense mechanism. The role of the other sRNA is unknown, although observed complementarities against particular mRNA sequences suggest an antisense mechanism. We suggest that the low level of sRNAs observed in B. burgdorferi is at least partly due to the presumed lack of both functional Hfq protein and RNase E activity.

  • 94.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carroll, James A
    Pinne, Marija
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Krum, Jonathan G
    Rosa, Patricia
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pleiotropic effects of inactivating a carboxyl-terminal protease, CtpA, in Borrelia burgdorferi2004In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 186, no 7, p. 2074-2084Article in journal (Refereed)
    Abstract [en]

    The aetiological agent of Lyme disease, Borrelia burgdorferi cycles between its tick vector and mammalian hosts, implying that it can sense different environments and consequently change the expression of genes encoding several surface-associated proteins. The genome of the type strain B. burgdorferi B31 has revealed 175 different gene families. The p13 gene, situated on the chromosome, encodes a channel-forming protein that belongs to the gene family 48 consisting of eight additional paralogous genes. The heterogeneity of the P13 protein from different Lyme disease Borrelia strains was investigated. The predicted surface-exposed domains are the most heterogeneous regions and contain probable epitopes of P13. The membrane-spanning architecture of P13 was determined and a model for the location of this protein in the outer membrane is presented. The transcription of the paralogues of gene family 48 during in vitro culturing and in a mouse infection model was also analysed. The bba01 gene is the only p13 paralogue present in all three Lyme-disease-causing genospecies; it is stable during cultivation in vitro and the BBA01 protein was expressed in all Borrelia strains investigated. Conversely, paralogues bbi31, bbq06 and bbh41 were only detected in B. burgdorferi and the corresponding plasmids harbouring bbi31 and bbh41 were lost during in vitro passage. Finally, p13 and bbi31 are the only members of gene family 48 that are transcribed in mice, suggesting their importance during mammalian infection.

  • 95.
    Östberg, Yngve
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Pinne, Marija
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Rosa, Patricia
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elimination of channel-forming activity by insertional inactivation of the p13 gene in Borrelia burgdorferi2002In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 184, no 24, p. 6811-6819Article in journal (Refereed)
    Abstract [en]

    P13 is a chromosomally encoded 13-kDa integral outer membrane protein of the Lyme disease agent, Borrelia burgdorferi. The aim of this study was to investigate the function of the P13 protein. Here, we inactivated the p13 gene by targeted mutagenesis and investigated the porin activities of outer membrane proteins by using lipid bilayer experiments. Channel-forming activity was lost in the p13 mutant compared to wild-type B. burgdorferi, indicating that P13 may function as a porin. We purified native P13 to homogeneity by fast performance liquid chromatography and demonstrated that pure P13 has channel-forming activity with a single-channel conductance in 1 M KCl of 3.5 nS, the same as the porin activity that was lost in the p13 mutant. Further characterization of the channel formed by P13 suggested that it is cation selective and voltage independent. In addition, no major physiological effects of the inactivated p13 gene could be detected under normal growth conditions. The inactivation of p13 is the first reported inactivation of a gene encoding an integral outer membrane protein in B. burgdorferi. Here, we describe both genetic and biophysical experiments indicating that P13 in B. burgdorferi is an outer membrane protein with porin activity.

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