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  • 301. Delguste, Martin
    et al.
    Peerboom, Nadia
    Le Brun, Gregoire
    Trybala, Edward
    Olofsson, Sigvard
    Bergström, Tomas
    Alsteens, David
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 3, p. 534-542Article in journal (Refereed)
    Abstract [en]

    Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.

  • 302. Dempsey, M P
    et al.
    Dobson, M
    Zhang, C
    Zhang, M
    Lion, C
    Gutiérrez-Martín, C B
    Iwen, P C
    Fey, P D
    Olson, M E
    Niemeyer, D
    Francesconi, S
    Crawford, R
    Stanley, M
    Rhodes, J
    Wagner, D M
    Vogler, A J
    Birdsell, D
    Keim, P
    Johansson, Anders
    Umeå University, Faculty of Medicine, Clinical Microbiology, Infectious Diseases.
    Hinrichs, S H
    Benson, A K
    Genomic deletion marking an emerging subclone of Francisella tularensis subsp. holarctica in France and the Iberian Peninsula.2007In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 73, no 22, p. 7465-70Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis subsp. holarctica is widely disseminated in North America and the boreal and temperate regions of the Eurasian continent. Comparative genomic analyses identified a 1.59-kb genomic deletion specific to F. tularensis subsp. holarctica isolates from Spain and France. Phylogenetic analysis of strains carrying this deletion by multiple-locus variable-number tandem repeat analysis showed that the strains comprise a highly related set of genotypes, implying that these strains were recently introduced or recently emerged by clonal expansion in France and the Iberian Peninsula.

  • 303.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Serotonin stimulates survival and proliferation of B-cell lymphomas: Effect on proliferation and expression of oncogenes upon inhibition of serotonin signaling in B-cell lymphoma cell lines2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 304. Derouin, Francis
    et al.
    Pelloux, H
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Petersen, Eskild
    Peyron, F
    Mathis, A
    van Gool, T
    Chiodini, P
    Junie, M
    Kortbeek, L
    Prevention of toxoplasmosis in transplant patients.2008In: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, ISSN 1469-0691, Vol. 14, no 12, p. 1089-101Article in journal (Refereed)
    Abstract [en]

    Toxoplasmosis is a life-threatening opportunistic infection that affects haematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. Its incidence in these patients is closely related to the prevalence of toxoplasmosis in the general population, which is high in Europe. In SOT recipients, toxoplasmosis results mainly from transmission of the parasite with the transplanted organ from a Toxoplasma-seropositive donor to a Toxoplasma-seronegative recipient. This risk is high in cases of transplantation of organs that are recognized sites of encystation of the parasite, e.g. the heart, and is markedly lower in other SOT recipients. Clinical symptoms usually occur within the first 3 months after transplantation, sometimes as early as 2 weeks post transplant, and involve febrile myocarditis, encephalitis or pneumonitis. In HSCT recipients, the major risk of toxoplasmosis results from the reactivation of a pre-transplant latent infection in seropositive recipients. The median point of disease onset is estimated at 2 months post transplant, with <10% of cases occurring before 30 days and 15-20% later than day 100. Toxoplasmosis usually manifests as encephalitis or pneumonitis, and frequently disseminates with multiple organ involvement. Diagnosis of toxoplasmosis is based on the demonstration of parasites or parasitic DNA in blood, bone marrow, cerebrospinal fluid, bronchoalveolar lavage fluid or biopsy specimens, and serological tests do not often contribute to the diagnosis. For prevention of toxoplasmosis, serological screening of donors and recipients before transplantation allows the identification of patients at higher risk of toxoplasmosis, i.e. seropositive HSCT recipients and mismatched (seropositive donor/seronegative recipients) SOT recipients. Preventing toxoplasmosis disease in those patients presently relies on prophylaxis via prescription of co-trimoxazole.

  • 305.
    Desso, Dawit Dejene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Jämförelse av Bruker Sepsityper-kit med in-house extraktionsmetoder för direkt bakterieidentifiering i positiva blododlingar2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 306.
    Desvars, Amélie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Furberg, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Epidemiology and Ecology of Tularemia in Sweden2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, p. 58-58Article in journal (Other academic)
  • 307.
    Desvars, Amélie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Furberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rydén, Patrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Epidemiology and Ecology of Tularemia in Sweden, 1984-20122015In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 21, no 1, p. 32-39Article in journal (Refereed)
    Abstract [en]

    The zoonotic disease tularemia is endemic in large areas of the Northern Hemisphere, but research is lacking on patterns of spatial distribution and connections with ecologic factors. To describe the spatial epidemiology of and identify ecologic risk factors for tularemia incidence in Sweden, we analyzed surveillance data collected over 29 years (1984-2012). A total of 4,830 cases were notified, of which 3,524 met all study inclusion criteria. From the first to the second half of the study period, mean incidence increased 10-fold, from 0.26/100,000 persons during 1984-1998 to 2.47/100,000 persons during 1999 2012 (p<0.001). The incidence of tularemia was higher than expected in the boreal and alpine ecologic regions (p<0.001), and incidence was positively correlated with the presence of lakes and rivers (p<0.001). These results provide a comprehensive epidemiologic description of tularemia in Sweden and illustrate that incidence is higher in locations near lakes and rivers.

  • 308.
    Desvars-Larrive, Amélie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Liu, X.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hjertqvist, M.
    Sjöstedt, A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    High-risk regions and outbreak modelling of tularemia in humans2017In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 145, no 3, p. 482-490Article in journal (Refereed)
    Abstract [en]

    Sweden reports large and variable numbers of human tularemia cases, but the high-risk regions are anecdotally defined and factors explaining annual variations are poorly understood. Here, high-risk regions were identified by spatial cluster analysis on disease surveillance data for 1984-2012. Negative binomial regression with five previously validated predictors (including predicted mosquito abundance and predictors based on local weather data) was used to model the annual number of tularemia cases within the high-risk regions. Seven high-risk regions were identified with annual incidences of 3.8-44 cases/100 000 inhabitants, accounting for 56.4% of the tularemia cases but only 9.3% of Sweden's population. For all high-risk regions, most cases occurred between July and September. The regression models explained the annual variation of tularemia cases within most high-risk regions and discriminated between years with and without outbreaks. In conclusion, tularemia in Sweden is concentrated in a few high-risk regions and shows high annual and seasonal variations. We present reproducible methods for identifying tularemia high-risk regions and modelling tularemia cases within these regions. The results may help health authorities to target populations at risk and lay the foundation for developing an early warning system for outbreaks.

  • 309. Dever, Thomas E
    et al.
    Yang, Weimin
    Åström, Stefan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Byström, Anders S
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Hinnebusch, A G
    Modulation of tRNA(iMet), eIF-2, and eIF-2B expression shows that GCN4 translation is inversely coupled to the level of eIF-2.GTP.Met-tRNA(iMet) ternary complexes1995In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 15, no 11, p. 6351-6363Article in journal (Refereed)
    Abstract [en]

    To understand how phosphorylation of eukaryotic translation initiation factor (eIF)-2 alpha in Saccharomyces cerevisiae stimulates GCN4 mRNA translation while at the same time inhibiting general translation initiation, we examined the effects of altering the gene dosage of initiator tRNA(Met), eIF-2, and the guanine nucleotide exchange factor for eIF-2, eIF-2B. Overexpression of all three subunits of eIF-2 or all five subunits of eIF-2B suppressed the effects of eIF-2 alpha hyperphosphorylation on both GCN4-specific and general translation initiation. Consistent with eIF-2 functioning in translation as part of a ternary complex composed of eIF-2, GTP, and Met-tRNA(iMet), reduced gene dosage of initiator tRNA(Met) mimicked phosphorylation of eIF-2 alpha and stimulated GCN4 translation. In addition, overexpression of a combination of eIF-2 and tRNA(iMet) suppressed the growth-inhibitory effects of eIF-2 hyperphosphorylation more effectively than an increase in the level of either component of the ternary complex alone. These results provide in vivo evidence that phosphorylation of eIF-2 alpha reduces the activities of both eIF-2 and eIF-2B and that the eIF-2.GTP. Met-tRNA(iMet) ternary complex is the principal component limiting translation in cells when eIF-2 alpha is phosphorylated on serine 51. Analysis of eIF-2 alpha phosphorylation in the eIF-2-overexpressing strain also provides in vivo evidence that phosphorylated eIF-2 acts as a competitive inhibitor of eIF-2B rather than forming an excessively stable inactive complex. Finally, our results demonstrate that the concentration of eIF-2-GTP. Met-tRNA(iMet) ternary complexes is the cardinal parameter determining the site of reinitiation on GCN4 mRNA and support the idea that reinitiation at GCN4 is inversely related to the concentration of ternary complexes in the cell.

  • 310. Dicks, Matthew DJ
    et al.
    Spencer, Alexandra J
    Edwards, Nick J
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bojang, Kalifa
    Gilbert, Sarah C
    Hill, Adrian VS
    Cottingham, Matthew G
    A novel chimpanzee adenovirus vector with low human seroprevalence: improved systems for vector derivation and comparative immunogenicity2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40385-Article in journal (Refereed)
    Abstract [en]

    Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent preexisting anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.

  • 311. Dillner, Joakim
    et al.
    Rebolj, Matejka
    Birembaut, Philippe
    Petry, Karl-Ulrich
    Szarewski, Anne
    Munk, Christian
    de Sanjose, Silvia
    Naucler, Pontus
    Lloveras, Belen
    Kjaer, Susanne
    Cuzick, Jack
    van Ballegooijen, Marjolein
    Clavel, Christine
    Iftner, Thomas
    Wadell, Göran
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study.2008In: BMJ (Clinical research ed.), ISSN 1468-5833, Vol. 337, p. a1754-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). DESIGN: Multinational cohort study with joint database analysis. SETTING: Seven primary HPV screening studies in six European countries. PARTICIPANTS: 24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. MAIN OUTCOME MEASURE: Long term cumulative incidence of CIN3+. RESULTS: The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. CONCLUSIONS: A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

  • 312.
    Dimova, Tanya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stenqvist, Ann-Christin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hedlund, Malin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strand, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples.2011In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 66, no Suppl 1, p. 44-56Article in journal (Refereed)
    Abstract [en]

    PROBLEM: Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women.

    METHOD OF STUDY: Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR.

    RESULTS: The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFβ1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells.

    CONCLUSION: (i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.

  • 313.
    Dirie, Jawhari
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Cytokinprofil i serum hos patienter med samhällsförvärvad pneumoni.2014Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 314. Dobler, G.
    et al.
    Bestehorn, M.
    Antwerpen, M.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Complete Genome Sequence of a Low-Virulence Tick-Borne Encephalitis Virus Strain2016In: Microbiology Resource Announcements, ISSN 2576-098X, Vol. 4, no 5, article id e01145-16Article in journal (Refereed)
    Abstract [en]

    We report here the complete genome sequence (GenBank accession no. KX268728) of tick-borne encephalitis strain HB171/11, isolated from an Ixodes ricinus tick from a natural focus where human neurological disease is rare. The strain shows unique characteristics in neuroinvasiveness and neurovirulence.

  • 315.
    Drobni, Peter
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Papillomavirus binding and entry: The heparan sulfate receptor and inhibition by lactoferrin2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Papillomaviruses (PVs) infect epithelial cells and are the main causative agent of cervical carcinoma. There are today more than a hundred different PV types and these can be divided into high risk and low risk types. They infect differentiating epithelial cells which make it cumbersome to propagate and produce human papillomavirus (HPV) virions. A common method to study HPV infection is to use HPV virus like particles (VLPs) produced in recombinant eukaryotic expression systems. Glycosaminoglycans (GAGs) have been described as an initial attachment receptor for several viruses. Our aim was to study the interactions between HPV VLPs and different GAGs to determine how these could affect binding and internalization. We found that soluble heparin was the best GAG inhibitor of HPV-16 VLP binding followed by heparan sulfate of mucosal origin. We could also see that CHO cells deficient in GAG expression had a reduced ability to bind VLPs, as did cells pretreated with heparinase III. Our results suggested a primary interaction between HPV and heparin sulfate. To be able to study the early steps of internalization we developed a method where we conjugated the CFDA-SE dye to the surface of VLPs. CFDA-SE is activated by cellular esterases inside the cell. This renders the particle fluorescent and thereby visible in flow cytometry analysis. With this new technique we found that entry of the mucosal HPV-6 and HPV-16 was inhibited by heparin. We could also detect differences between mucosal HPV-16 and cutaneous HPV-5 when these where pre-incubated together with GAGs. The cutaneous PV type was not inhibited by heparin to as high degree as the mucosal type. This might be explained by charge differences in the capsid. The mucosal capsid seems to be more positively charged than the epithelial type which should result in a higher affinity for the negatively charged GAGs. Also, we report for the first time that HPV-5 uses a clathrin mediated internalization process. It has been reported for other viruses such as herpes simplex virus (HSV) that lactoferrin, a protein found in high concentrations in breast milk and vaginal fluids could inhibit infection. Interestingly, HSV also use heparan sulfate as a primary attachment molecule. We wanted to investigate if lactoferrin and lactoferricin could have an effect on HPV binding and internalization. We pre-treated HPV-16 VLPs with lactoferrin of bovine or human origin before infection. After incubation we could detect reduced levels of both bound and internalized HPV VLPs to HaCaT cells. In this case, lactoferrin of bovine origin proved to be more efficient in inhibiting both binding and internalization. To further investigate this we used the N-terminal part of lactoferrin, lactoferricin, to study any possible inhibitory effects. Here we found that lactoferricin of bovine origin was a more potent inhibitor of binding, while human lactoferricin was more effective in inhibiting internalization. This could in part be explained by folding differences between these two related proteins. This work further strengthens the proposed interaction between HS and PV for initial interaction and for the first time show charge depending differences between cutaneous and mucosal type binding and internalization and also that lactoferrin and lactoferricin, parts of the innate immune system inhibit PV binding and internalization in vivo.

  • 316.
    Drobni, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    McMillan, Nigel
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Carboxy-fluorescein diacetate, succinimidyl ester labeled papillomavirus virus-like particles fluoresce after internalization and interact with heparan sulfate for binding and entry2003In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 310, no 1, p. 163-172Article in journal (Refereed)
    Abstract [en]

    Human papillomaviruses (HPVs) infect epithelial cells and are associated with genital carcinoma. Most epithelial cell lines express cell-surface glycosaminoglycans (GAGs) usually found attached to the protein core of proteoglycans. Our aim was to study how GAGs influenced HPV entry. Using a human keratinocyte cell line (HaCaT), preincubation of HPV virus-like particles (VLPs) with GAGs showed a dose-dependent inhibition of binding. The IC(50) (50% inhibition) was only 0.5 microg/ml for heparin, 1 microg/ml for dextran sulfate, and 5-10 microg/ml for heparan sulfate from mucosal origin. Mutated chinese hamster ovary (CHO) cell lines lacking heparan sulfate or all GAGs were unable to bind HPV VLPs. Here we also report a method to study internalization by using VLPs labeled with carboxy-fluorescein diacetate, succinimidyl ester, a fluorochrome that is only activated after cell entry. Pretreatment of labeled HPV VLPs with heparin inhibited uptake, suggesting a primary interaction between HPV and cell-surface heparan sulfate.

  • 317.
    Drobni, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Näslund, Jonas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lactoferrin inhibits human papillomavirus binding and uptake in vitro.2004In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 64, no 1, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Lactoferrin (LF), a member of the transferrin family, is a bi-globular protein secreted in milk, saliva, tears, seminal fluid, endocervix and vaginal secretions. LF is an important player in the defence against pathogenic microorganisms and has also been shown to have activity against several viruses including herpesvirus, adenovirus, rotavirus and poliovirus. The antiviral activity of LF is directed against the early steps of viral infection and the LF antiviral effect against herpesvirus is mediated through LF binding to the herpesvirus receptor heparan sulfate. Human papillomavirus (HPV) causes genital warts and is a prerequisite for cervical cancer. HPV can also use heparan sulfate on the cell surface as a receptor. We studied the inhibition by LF on HPV entry by incubating HaCaT cells and HPV-16 virus-like particles (VLPs) with either human (HLF) or bovine lactoferrin (BLF). LF inhibited internalization of HPV-16 particles using CFDA-SE-labelled VLPs that only fluoresce after internalisation. By using a western blot assay we also found dose-dependent LF inhibition of HPV-16 VLP binding to the HaCaT cell surface. BLF was a more potent inhibitor of HPV entry than human LF. It was also clear that LF acted early in the HPV uptake process.

  • 318.
    Drobni, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Näslund, Jonas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Jenssen, Håvard
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    The anti-HPV activity of human and bovine lactoferricin.Manuscript (Other academic)
  • 319.
    Dudarev, Alexey A
    et al.
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Alloyarov, Pavel R
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Chupakhin, Valery S
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Dushkina, Eugenia V
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Sladkova, Yuliya N
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Dorofeyev, Vitaliy M
    Dubna City Hospital, Moscow oblast, Russia.
    Kolesnikova, Tatijana A
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Fridman, Kirill B
    Northwest Public Health Research Center, St. Petersburg, Russia.
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Arctic Research Centre at Umeå University.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Arctic Research Centre at Umeå University.
    Food and water security issues in Russia I: Food security in the general population of the Russian Arctic, Siberia and the Far East2013In: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 72, p. 1-10, article id 21848Article in journal (Refereed)
    Abstract [en]

    Background. Problems related to food security in Russian Arctic (dietary imbalance, predominance ofcarbohydrates, shortage of milk products, vegetables and fruits, deficit of vitamins and microelements,chemical, infectious and parasitic food contamination) have been defined in the literature. But no standardprotocol of food security assessment has been used in the majority of studies.

    Objectives. Our aim was to obtain food security indicators, identified within an Arctic collaboration,for selected regions of the Russian Arctic, Siberia and the Far East, and to compare food safety in theseterritories.

    Study design and methods. In 18 regions of the Russian Arctic, Siberia and the Far East, the followingindicators of food security were analyzed: food costs, food consumption, and chemical and biological foodcontamination for the period 2000-2011.

    Results. Food costs in the regions are high, comprising 2343% of household income. Only 4 out of 10 foodgroups (fish products, cereals, sugar, plant oil) are consumed in sufficient amounts. The consumption of milkproducts, eggs, vegetables, potatoes, fruits (and berries) is severely low in a majority of the selected regions.There are high levels of biological contamination of food in many regions. The biological and chemicalcontamination situation is alarming, especially in Chukotka. Only 7 food pollutants are under regularcontrol; among pesticides, only DDT. Evenki AO and Magadan Oblast have reached peak values in foodcontaminants compared with other regions. Mercury in local fish has not been analyzed in the majority of theregions. In 3 regions, no monitoring of DDToccurs. Aflatoxins have not been analyzed in 5 regions. Nitrateshad the highest percentage in excess of the hygienic threshold in all regions. Excesses of other pollutants indifferent regions were episodic and as a rule not high.

    Conclusion. Improvement of the food supply and food accessibility in the regions of the Russian Arctic,Siberia and the Far East is of utmost importance. Both quantitative and qualitative control of chemical andbiological contaminants in food is insufficient and demands radical enhancement aimed at improving foodsecurity.

  • 320. Dudarev, Alexey
    et al.
    Dorofeyey, Vitaliy
    Dushkina, Eugenia
    Alloyarov, Pavel
    Chupakhin, Valery
    Sladkova, Yuliya
    Kolesnikova, Tatjana
    Fridman, Kirill
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Evengård, Birgitta
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Food and water security issues in Russia III: food- and waterborne diseases in the Russian Arctic, Siberia and the Far East, 2000-20112013In: International Journal of Circumpolar Health, ISSN 2242-3982, E-ISSN 2242-3982, Vol. 72, p. 21856-Article in journal (Refereed)
    Abstract [en]

    Background. The food- and waterborne disease situation in Russia requires special attention. Poor quality of centralized water supplies and sewage systems, biological and chemical contamination of drinking water, as well as contamination of food products, promote widespread infectious diseases, significantly exceeding nationwide rates in the population living in the two-thirds of Russian northern territories.Objectives. The general aim was to assess the levels of food- and waterborne diseases in selected regions of Russian Arctic, Siberia and the Far East (for the period 2000ᅵ2011), and to compare disease levels among regions and with national levels in Russia.Study design and methods. This study is the first comparative assessment of the morbidity in these fields of the population of 18 selected regions of Russian Arctic, Siberia and the Far East, using official statistical sources. The incidences of infectious and parasitic food- and waterborne diseases among the general population (including indigenous peoples) have been analyzed in selected regions (per 100,000 of population, averaged for 2000ᅵ2011).Results. Among compulsory registered infectious and parasitic diseases, there were high rates and widespread incidences in selected regions of shigellosis, yersiniosis, hepatitis A, tularaemia, giardiasis, enterobiasis, ascariasis, diphyllobothriasis, opistorchiasis, echinococcosis and trichinellosis.Conclusion. Incidences of infectious and parasitic food- and waterborne diseases in the general population of selected regions of the Russian Arctic, Siberia and the Far East (2000ᅵ2011) are alarmingly high. Parallel solutions must be on the agenda, including improvement of sanitary conditions of cities and settlements in the regions, modernization of the water supply and of the sewage system. Provision and monitoring of the quality of the drinking water, a reform of the general healthcare system and the epidemiological surveillance (including gender-divided statistics), enhancement of laboratory diagnostics and the introduction of preventive actions are urgently needed.

  • 321. Dudarev, Alexey
    et al.
    Dushkina, Eugenia
    Sladkova, Yuliya
    Alloyarov, Pavel
    Chupakhin, Valeriy
    Dorofeyey, Vitaliy
    Kolesnikova, Tatijana
    Fridman, Kirill
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Arctic Research Centre at Umeå University.
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Food and water security issues in Russia II: Water security in general population of Russian Arctic, Siberia and Far East, 2000-20112013In: International Journal of Circumpolar Health, ISSN 2242-3982, E-ISSN 2242-3982, Vol. 72, p. 22646-Article in journal (Refereed)
    Abstract [en]

    Background. Poor state of water supply systems, shortage of water purification facilities and disinfection systems, low quality of drinking water generally in Russia and particularly in the regions of the Russian Arctic, Siberia and Far East have been defined in the literature. However, no standard protocol of water security assessment has been used in the majority of studies.Study design and methods. Uniform water security indicators collected from Russian official statistical sources for the period 2000ᅵ2011 were used for comparison for 18 selected regions in the Russian Arctic, Siberia and Far East. The following indicators of water security were analyzed: water consumption, chemical and biological contamination of water reservoirs of Categories I and II of water sources (centralized ᅵ underground and surface, and non-centralized) and of drinking water.Results. Water consumption in selected regions fluctuated from 125 to 340 L/person/day. Centralized water sources (both underground and surface sources) are highly contaminated by chemicals (up to 40ᅵ80%) and biological agents (up to 55% in some regions), mainly due to surface water sources. Underground water sources show relatively low levels of biological contamination, while chemical contamination is high due to additional water contamination during water treatment and transportation in pipelines. Non-centralized water sources are highly contaminated (both chemically and biologically) in 32ᅵ90% of samples analyzed. Very high levels of chemical contamination of drinking water (up to 51%) were detected in many regions, mainly in the north-western part of the Russian Arctic. Biological contamination of drinking water was generally much lower (2.5ᅵ12%) everywhere except Evenki AO (27%), and general and thermotolerant coliform bacteria predominated in drinking water samples from all regions (up to 17.5 and 12.5%, correspondingly). The presence of other agents was much lower: Coliphages ᅵ 0.2ᅵ2.7%, Clostridia spores, Giardia cysts, pathogenic bacteria, Rotavirus ᅵ up to 0.8%. Of a total of 56 chemical pollutants analyzed in water samples from centralized water supply systems, 32 pollutants were found to be in excess of hygienic limits, with the predominant pollutants being Fe (up to 55%), Cl (up to 57%), Al (up to 43%) and Mn (up to 45%).Conclusion. In 18 selected regions of the Russian Arctic, Siberia and Far East Category I and II water reservoirs, water sources (centralized ᅵ underground, surface; non-centralized) and drinking water are highly contaminated by chemical and biological agents. Full-scale reform of the Russian water industry and water security system is urgently needed, especially in selected regions.

  • 322. Dudnyk, Andrii
    et al.
    Rzhepishevska, Olena
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rogach, Kostiantyn
    Kutsyna, Galyna
    Lange, Christoph
    Multidrug-resistant tuberculosis in Ukraine at a time of military conflict2015In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 19, no 4, p. 492-493Article in journal (Refereed)
  • 323. Duffy, Margaret R.
    et al.
    Alonso-Padilla, Julio
    John, Lijo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Khan, Selina
    Ballmann, Monika Z.
    Lipiec, Agnieszka
    Heemskerk, Evert
    Custers, Jerome
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Havenga, Menzo
    Baker, Andrew H.
    Lemckert, Angelique
    Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 562018In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 99, p. 135-147Article in journal (Refereed)
    Abstract [en]

    The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.

  • 324.
    Dwibedi, Chinmay Kumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Swedish Defence Research Agency.
    Francisella tularensis: persistence, dissemination and source attribution: a theoretical and computational approach2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The bacterium Francisella tularensis causing tularemia in humans and other mammals displays little genetic diversity among genomes across temporal and spatial scales. F. tularensis infects humans with an extremely low infectious dose and causes natural seasonal tularemia outbreaks. During the Cold War, this bacterium was developed as a biological weapon.

    In paper I, we aimed at investigating the genetic diversity of F. tularensis over space and time and were especially interested in the influence of spatial dispersal on the genetic diversity. By analyses of single-nucleotide polymorphisms (SNPs) among 205 F. tularensis genomes, we found that tularemia had moved from East to West over the European continent by dispersal patterns characterized by multiple long-range dispersal events. Evolutionary rate estimates based on the year of bacterial isolation from 1947 to 2012 indicated non-measurable rates. In outbreak areas with multiple recent outbreaks, however, there was a measurable rate of 0.4 SNPs/genome/year indicating that in areas with more intense disease activity, there is a detectable evolutionary rate. The findings suggest that long-range geographical dispersal events and mostly very low evolutionary rates are important factors contributing to a very low genetic diversity of F. tularensis populations.

    In paper II, we focused on a geographically restricted area with a history of frequent tularemia outbreaks to study F. tularensis persistence. By analyzing F. tularensis genomes from 138 individuals infected from 1994 to 2010 in Örebro County in Sweden and performing a long-term laboratory storage experiment, we explored the microbial population concept of a pathogen seed-bank. We found that eight indistinguishable genomes – each of them defined by no SNPs across 1.65 million whole-genome nucleotides – locally persisted over 2-9 years. We found unmeasurable SNP accumulation rates and overlapping bacterial generations among the outbreak genomes and that F. tularensis survived in saline for four years without nutrients. By these findings, and analyses of nucleotide substitution patterns, we suggest that a pathogen seed-bank effect is an important feature of F. tularensis ecology influencing genetic diversity.

    In paper III, we developed a new concept for source attribution of a F. tularensis sample. We aimed to identify genetic variation that is characteristic to laboratory culturing and we used culture amplification to identify genetic variation present at exceedingly low frequencies in a sample. Based on a biological enrichment scheme followed by high-throughput sequencing, we could track genetic variation back to a source sample. These results suggest that the concept has potential for linking a F. tularensis sample to its laboratory source sample.

    Taken together, the results presented in this thesis provide new understanding of the dissemination patterns and local persistence of tularemia. This is important for the interpretation of molecular epidemiology investigations of the disease. In a wider context, the results demonstrate how spatial dispersal and a microbial seed-bank effect may contribute to the diversity of a disease-causing agent. Finally, we have described a promising concept for source attribution of F. tularensis samples

  • 325.
    Dwibedi, Chinmay Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Division of CBRN Security and Defence, Swedish Defense Research Agency, Umeå, Sweden.
    Birdsell, Dawn
    Larkeryd, Adrian
    Myrtennas, Kerstin
    Ohrman, Caroline
    Nilsson, Elin
    Karlsson, Edvin
    Hochhalter, Christian
    Rivera, Andrew
    Maltinsky, Sara
    Bayer, Brittany
    Keim, Paul
    Scholz, Holger C.
    Tomaso, Herbert
    Wittwer, Matthias
    Beuret, Christian
    Schuerch, Nadia
    Pilo, Paola
    Hernandez Perez, Marta
    Rodriguez-Lazaro, David
    Escudero, Raquel
    Anda, Pedro
    Forsman, Mats
    Wagner, David M.
    Larsson, Par
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Long-range dispersal moved Francisella tularensis into Western Europe from the East2016In: Microbial Genomics, ISSN 2057-5858, Vol. 2, no 12Article in journal (Refereed)
    Abstract [en]

    For many infections transmitting to humans from reservoirs in nature, disease dispersal patterns over space and time are largely unknown. Here, a reversed genomics approach helped us understand disease dispersal and yielded insight into evolution and biological properties of Francisella tularensis, the bacterium causing tularemia. We whole-genome sequenced 67 strains and characterized by single-nucleotide polymorphism assays 138 strains, collected from individuals infected 1947-2012 across Western Europe. We used the data for phylogenetic, population genetic and geographical network analyses. All strains (n= 205) belonged to a monophyletic population of recent ancestry not found outside Western Europe. Most strains (n= 195) throughout the study area were assigned to a star-like phylogenetic pattern indicating that colonization of Western Europe occurred via clonal expansion. In the East of the study area, strains were more diverse, consistent with a founder population spreading from east to west. The relationship of genetic and geographic distance within the F. tularensis population was complex and indicated multiple long-distance dispersal events. Mutation rate estimates based on year of isolation indicated null rates; in outbreak hotspots only, there was a rate of 0.4 mutations/genome/year. Patterns of nucleotide substitution showed marked AT mutational bias suggestive of genetic drift. These results demonstrate that tularemia has moved from east to west in Europe and that F. tularensis has a biology characterized by long-range geographical dispersal events and mostly slow, but variable, replication rates. The results indicate that mutation-driven evolution, a resting survival phase, genetic drift and long-distance geographical dispersal events have interacted to generate genetic diversity within this species.

  • 326.
    Dwibedi, Chinmay Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Larsson, P.
    Lindgren, P.
    Myrtennäs, K.
    Granberg, M.
    Larsson, E.
    Öhrman, C.
    Sjödin, A.
    Stenberg, P.
    Ahlinder, J.
    Forsman, M.
    Johansson, A.
    Biological amplification of low frequency mutations for source attribution of Francisella tularensisManuscript (preprint) (Other academic)
  • 327.
    Dwibedi, Chinmay Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Myrtennäs, K.
    Thelaus, J.
    Öhrman, C.
    Lärkeryd, A.
    Birdsell, D.
    Keim, P.
    Bäckman, S.
    Noppa, L.
    Näslund, J.
    Lundmark, E.
    Vidman, L.
    Lindgren, P.
    Eliasson, H.
    Fredlund, H.
    Ryden, P.
    Larsson, P.
    Wagner, D.
    Forsman, M.
    Johansson, A.
    Tularemia outbreaks are caused by infective pathogen seedbanksManuscript (preprint) (Other academic)
  • 328.
    Dzanovic, Elvira
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Epidemiologisk klassificering av Staphylococcus epidermidis med Matrix- Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF)2015Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 329.
    Ebeling, Rebecca
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Etablering av fluorescens-baserad western blot detektion av virus i cellkultur2019Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 330. Ecke, Frauke
    et al.
    Mahani, Seyed Alireza Nematollahi
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Hörnfeldt, Birger
    Khalil, Hussein
    Wildfire-induced short-term changes in a small mammal community increase prevalence of a zoonotic pathogen?2019In: Ecology and Evolution, ISSN 2045-7758, E-ISSN 2045-7758, Vol. 9, no 22, p. 12459-12470Article in journal (Refereed)
    Abstract [en]

    Natural disturbances like droughts and fires are important determinants of wildlife community structure and are suggested to have important implications for prevalence of wildlife-borne pathogens. After a major wildfire affecting >1,600 ha of boreal forest in Sweden in 2006, we took the rare opportunity to study the short-term response (2007-2010 and 2015) of small mammal community structure, population dynamics, and prevalence of the Puumala orthohantavirus (PUUV) hosted by bank voles (Myodes glareolus). We performed snap-trapping in permanent trapping plots in clear-cuts (n = 3), unburnt reference forests (n = 7), and the fire area (n = 7) and surveyed vegetation and habitat structure. Small mammal species richness was low in all habitats (at maximum three species per trapping session), and the bank vole was the only small mammal species encountered in the fire area after the first postfire year. In autumns of years of peak rodent densities, the trapping index of bank voles was lowest in the fire area, and in two of three peak-density years, it was highest in clear-cuts. Age structure of bank voles varied among forest types with dominance of overwintered breeders in the fire area in the first postfire spring. PUUV infection probability in bank voles was positively related to vole age. Infection probability was highest in the fire area due to low habitat complexity in burnt forests, which possibly increased encounter rate among bank voles. Our results suggest that forest fires induce cascading effects, including fast recovery/recolonization of fire areas by generalists like bank voles, impoverished species richness of small mammals, and altered prevalence of a rodent-borne zoonotic pathogen. Our pilot study suggests high human infection risk upon encountering a bank vole in the fire area, however, with even higher overall risk in unburnt forests due to their higher vole numbers.

  • 331.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Improved diagnosis and prediction of community-acquired pneumonia2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Although there is wide variation in the microbial etiology, CAP may manifest with similar symptoms, making institution of proper treatment challenging. Therefore, etiological diagnosis is important to ensure that correct treatment and necessary infection control measures are instituted. This provides a challenge for conventional microbial diagnostic methods, typically based on culture and direct antigen tests. Moreover, existing molecular biomarkers have poor prognostic value. Few studies have investigated the global metabolic response during infection and virtually nothing is known about early responses after the start of antimicrobial treatment. The aim of this work was to improve diagnostic and predictive methods for CAP.

    In paper I, a qPCR panel targeting 15 pathogens known to cause CAP was developed and evaluated. It combined identification of bacterial pathogens and viruses in the same diagnostic platform. The method proved to be robust and the results consistent with those obtained by standard methods. The panel approach, compared to conventional, selective diagnostics, detected a larger number of pathogens. In Paper II, whole blood samples from 65 patients with bacteremic sepsis were analyzed for metabolite profiles. Forty-nine patients with symptoms of sepsis, but later attributed to other diagnoses, were matched according to age and sex and served as a control group. Six metabolites were identified, all of which predicted growth of bacteria in blood culture. One of the metabolites, myristic acid, alone predicted bacteremic sepsis with a sensitivity of 100% and a specificity of 95%. Paper III and IV were based on a clinical study enrolling 35 patients with suspected CAP in need of hospital care. The aim was to study the metabolic response during the early phase of acute infection. The qPCR panel developed in Paper I was used to obtain the microbial etiological diagnosis. Paper IV focused on the global metabolic response and highlighted the dynamics of changes in major metabolic pathways during early recovery. A specific metabolite pattern for M. pneumoniae etiology was found. Four metabolites accurately predicted all but one patient as either M. pneumoniae etiology or not. Paper III looked at phospholipid levels during the first 48 hours after hospital admission. It was found that all major phospholipid species, especially the lysophosphatidyl-cholines, were pronouncedly decreased during acute infection. Levels started to increase the day after admission, reaching statistical significance at 48 hours. Paper II-IV showed that metabolomics might be used to study a number of different aspects of infection, such as etiology, disease progress and recovery. Knowledge of the metabolic profiles of patients may not only be utilized for biomarker discovery, as proposed in this work, but also for the future development of targeted therapies and supportive treatment.

  • 332.
    Edin, Alicia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Koskiniemi, Satu
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Development and Laboratory Evaluation of a Real-Time PCR Assay for Detecting Viruses and Bacteria of Relevance for Community-Acquired Pneumonia2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 3, p. 315-324Article in journal (Refereed)
    Abstract [en]

    Community-acquired pneumonia may present with similar clinical symptoms, regardless of viral or bacterial cause. Diagnostic assays are needed to rapidly discriminate between causes, because this will guide decisions on appropriate treatment. Therefore, a quantitative real-time PCR (qPCR) assay with duplex reactions targeting eight bacteria and six viruses was developed. Technical performance was examined with linear plasmids. Upper and Lower respiratory tract specimens were used to compare the qPCR assay with standard microbiological methods. The limit of detection was 5 to 20 DNA template copies with approximately 1000-fold differences in concentrations of the two competing templates. SDs for positive controls were <5%. The use of the qPCR assay resulted in 113 positive identifications in 94 respiratory specimens compared with 38 by using standard diagnostics. Diagnostic accuracy of the qPCR assay varied between 60% positive agreement with standard tests for Streptococcus pneumoniae and 100% for Mycoplasma pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus. Negative percentage of agreement was >95% for M. pneumoniae, Streptococcus pyogenes, respiratory syncytial virus, and influenza A virus; whereas it was only 56% for Haemophilus influenzae. Multiple microbial agents were identified in 19 of 44 sputum and 19 of 50 nasopharynx specimens. We conclude that in parallel qPCR detection of the targeted respiratory bacteria and viruses is feasible. The results indicate good technical performance of the assay in clinical specimens.

  • 333.
    Edin, Alicia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kauppi, Anna M.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Müller, Daniel C.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johansson, Anders F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Metabolomic Analysis of Sera from Patients with Community-Acquired PneumoniaManuscript (preprint) (Other academic)
  • 334.
    Edsborg, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Allelfrekvensen av SNV rs113247976 C>T i KIF5A genen: Regionala skillnader i den svenska populationen2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 335. Edvinsson, Benjamin
    et al.
    Dardé, M-L
    Pelloux, H
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rapid genotyping of Toxoplasma gondii by pyrosequencing.2007In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 13, no 4, p. 424-9Article in journal (Refereed)
    Abstract [en]

    Most human infections with the protozoan parasite Toxoplasma gondii are asymptomatic, but severe symptoms can occur in immunocompromised patients, in developing foetuses, and in ocular infections in immunocompetent individuals. The majority of T. gondii strains can be divided into three main lineages, denoted types I, II and III, which are known to cause different clinical presentations. Simple molecular methods with the capacity to discriminate rapidly among strains may help to predict the course of infection and influence the choice of treatment. In the present study, real-time PCR followed by pyrosequencing was used to discriminate among types I, II and III by analysis of two single nucleotide polymorphisms in the GRA6 gene. Twenty-one isolates of T. gondii characterised previously were analysed. Three different GRA6 alleles detected by the pyrosequencing technique identified types I, II and III isolates correctly, while four atypical isolates possessed either the GRA6 allele 1 or the GRA6 allele 3. Reproducibility was 100%, and typeability, when including atypical strains, was 81%. It was also possible to discriminate a mixture of two genotypes. The method was used to identify GRA6 type II in blood and lung tissue from an allogeneic transplant recipient with toxoplasmosis.

  • 336.
    Edvinsson, Benjamin
    et al.
    Centre for Microbiological Preparedness, Swedish Institute for Infectious Diseases Control.
    Lappalainen, Maija
    Laboratory Services, Dept Virology, Helsiniki University.
    Anttila, Veli-Jukka
    Div Internal Medicine, Dept Infectious Diseases, Helsinki University.
    Paetau, Anders
    Dept Pathology, Helsinki University.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Toxoplasmosis in immunocompromized patients2009In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 41, no 5, p. 368-371Article in journal (Refereed)
    Abstract [en]

    Infection with the cosmopolitan parasite Toxoplasma gondii is often associated with severe consequences and a high mortality rate in immunocompromized patients. Non-specific symptoms make diagnosis challenging. Monitoring of patients at risk is of value. We here present 8 cases of toxoplasmosis in immunocompromized patients with suggestions for preventive monitoring.

  • 337. Edvinsson, Benjamin
    et al.
    Lundquist, Jessica
    Ljungman, Per
    Ringdén, Olle
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    A prospective study of diagnosis of Toxoplasma gondii infection after bone marrow transplantation.2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 5, p. 345-51Article in journal (Refereed)
    Abstract [en]

    Active infection with Toxoplasma gondii in immunocompromised transplant recipients can lead to toxoplasmosis, which may have a rapid disease course and in some cases be fatal. It is of paramount importance to diagnose toxoplasmosis at an early stage, and to initiate specific treatment to improve the outcome. Polymerase chain reaction (PCR) is today the primary diagnostic tool to diagnose toxoplasmosis in immunocompromised patients. Timely diagnosis may, however, be difficult if toxoplasmosis is at first asymptomatic. To investigate the magnitude of toxoplasmosis after bone marrow transplantation (BMT), we conducted a screening study by PCR where 21 autologous and 12 allogeneic BMT recipients were included. Peripheral blood samples were taken one week prior to BMT; thereafter, blood samples were drawn weekly for the first 6 months, and monthly up to one year after BMT. The samples were analyzed by conventional PCR and real-time PCR. T. gondii DNA was detected in peripheral blood from one patient 5 days post allogeneic BMT. There were no clinical signs of toxoplasmosis. Medical records were reviewed and showed a previously undiagnosed eye infection in another allogeneic BMT recipient. These two patients were seropositive for T. gondii. We concluded that monitoring for T. gondii DNA in peripheral blood samples using PCR might be a valuable method for identifying toxoplasma-seropositive stem cell transplant recipients.

  • 338.
    Egorova, Olga
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schneede, Jørn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Hägglöf, Bruno
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Bölte, Sven
    Domellöf, Erik
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Ivars A'roch, Barbro
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ueland, Per Magne
    Silfverdal, Sven-Arne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers2020In: Molecular Autism, ISSN 2040-2392, Vol. 11, article id 7Article in journal (Refereed)
    Abstract [en]

    Background: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis.

    Methods: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation.

    Results: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring.

    Conclusions: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

  • 339.
    Einarsdottir, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Nilsson-Ardnor, Sofie
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research, Umeå University.
    Penha-Goncalves, Carlos
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Gulbenkian Institute for Science, Oeiras, Portugal.
    Lind, Lisbet
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Unit for Genome Research, Umeå University.
    Holmgren, Gösta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Unit for Genome Research.
    The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease2003In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 11, no 1, p. 81-84Article in journal (Refereed)
    Abstract [en]

    We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

  • 340. Ejrnaes, Karen
    et al.
    Sandvang, Dorthe
    Lundgren, Bettina
    Ferry, Sven
    Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Holm, Stig
    Göteborgs Universitet.
    Monsen, Tor
    Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Lundholm, Rolf
    Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Clinical Bacteriology.
    Frimodt-Moller, Niels
    Pulsed-field gel electrophoresis typing of Escherichia coli strains from samples collected before and after pivmecillinam or placebo treatment of uncomplicated community-acquired urinary tract infection in women.2006In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 44, no 5, p. 1776-81Article in journal (Refereed)
    Abstract [en]

    The primary infecting Escherichia coli strains from 156 women with community-acquired uncomplicated urinary tract infection (UTI) randomized to pivmecillinam or placebo and the E. coli strains causing UTI at two follow-up visits were typed using pulsed-field gel electrophoresis (PFGE). In the pivmecillinam treatment group PFGE showed that among patients having a negative urine culture at the first follow-up 77% (46/60) had a relapse with the primary infecting E. coli strain and 23% (14/60) had reinfection with a new E. coli strain at the second follow-up. Among patients having E. coli at the first follow-up PFGE showed that 80% (32/40) had persistence with the primary infecting E. coli strain, 15% (6/40) had reinfection with a new E. coli strain, and 5% (2/40) had different E. coli strains at the two follow-up visits (one had reinfection followed by relapse, and the other had persistence followed by reinfection). In the placebo group the majority had E. coli at the first follow-up. PFGE showed that among these patients 96% (50/52) had persistence with the primary infecting E. coli strain and 4% (2/50) had different E. coli strains at the two follow-up visits (both had persistence followed by reinfection). The finding that the majority of UTIs at follow-up are caused by the primary infecting E. coli strain supports the theory of a vaginal and rectal reservoir but could also support the recent discovery that E. coli strains are able to persist in the bladder epithelium despite appropriate antibiotic treatment, constituting a reservoir for recurrent UTI.

  • 341.
    Ekestubbe, Sofie
    et al.
    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).
    Bröms, Jeanette E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Edgren, Tomas
    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).
    Fällman, Maria
    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).
    Francis, Matthew S.
    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).
    Forsberg, Åke
    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).
    The amino-terminal part of the needle-tip translocator LcrV of Yersinia pseudotuberculosis is required for early targeting of YopH and in vivo virulence2016In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 6, article id 175Article in journal (Refereed)
    Abstract [en]

    Type III secretion systems (T3SS) are dedicated to targeting anti-host effector proteins into the cytosol of the host cell to promote bacterial infection. Delivery of the effectors requires three specific translocator proteins, of which the hydrophilic translocator, LcrV, is located at the tip of the T3SS needle and is believed to facilitate insertion of the two hydrophobic translocators into the host cell membrane. Here we used Yersinia as a model to study the role of LcrV in T3SS mediated intracellular effector targeting. Intriguingly, we identified N-terminal IcrV mutants that, similar to the wild-type protein, efficiently promoted expression, secretion and intracellular levels of Yop effectors, yet they were impaired in their ability to inhibit phagocytosis by J774 cells. In line with this, the YopH mediated dephosphorylation of Focal Adhesion Kinase early after infection was compromised when compared to the wild type strain. This suggests that the mutants are unable to promote efficient delivery of effectors to their molecular targets inside the host cell upon host cell contact. The significance of this was borne out by the fact that the mutants were highly attenuated for virulence in the systemic mouse infection model. Our study provides both novel and significant findings that establish a role for LcrV in early targeting of effectors in the host cell.

  • 342.
    Ekici, Rifat
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B cells in Type 1 diabetes: studies on cell surface antibody binding2010Licentiate thesis, monograph (Other academic)
  • 343.
    Ekici, Rifat
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Enhanced capture of extramembranous IgM and IgG on B cells in the NOD mouse: implications for immune complex trapping2009In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 21, no 5, p. 533-541Article in journal (Refereed)
    Abstract [en]

    Binding of various antibody isotypes to B cells through either FcgammaRs or complement receptors has been attributed to play several roles, e.g. in immune complex (IC) transportation and regulation of B cell receptor signaling. We have revealed a novel B cell intrinsic receptor for IgM and IgG which is present in C57BL/6 (B6) mice and is more abundant in non-obese diabetic (NOD) mice. As a consequence, the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared with B6 mice. The effect of this aberration was that all B cells in peripheral blood of (NOD.IgH(a) x B6(IgH(b)))F(1) mice carried both IgM allotypes on their surface. In addition, analysis of IC binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with B6. We hypothesize that this novel Ig-binding receptor is part of the normal immune system function. The aberrant function in the NOD mouse could contribute to the development of Type 1 diabetes by altering normal B cell functions such as activation, IC transportation and B cell homeostasis.

  • 344.
    Eklund, Lina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cytostatikabehandling av kolorektalcancer-celler med olika genetisk bakgrund: Genetisk bakgrund har betydelse för effekten av behandlingen2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 345.
    Elebrink, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Utveckling av en in vitro-modell för studier av sekundärt immunsvar mot Francisella tularensis2019Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 346.
    Elfving, Adam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Förekomst av myggburna virus i Västerbotten2017Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 347.
    Elfving, Caitlin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Förekomst av multiresistenta koagulasnegativa stafylokocker2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 348. Elfving, Karin
    et al.
    Olsen, Björn
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Waldenström, Jonas
    Lundkvist, Åke
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Mejlon, Hans
    Nilsson, Kenneth
    Dissemination of spotted fever rickettsia agents in Europe by migrating birds2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8572-Article in journal (Refereed)
    Abstract [en]

    Migratory birds are known to play a role as long-distance vectors for many microorganisms. To investigate whether this is true of rickettsial agents as well, we characterized tick infestation and gathered ticks from 13,260 migratory passerine birds in Sweden. A total of 1127 Ixodes spp. ticks were removed from these birds and the extracted DNA from 957 of them was available for analyses. The DNA was assayed for detection of Rickettsia spp. using real-time PCR, followed by DNA sequencing for species identification. Rickettsia spp. organisms were detected in 108 (11.3%) of the ticks. Rickettsia helvetica, a spotted fever rickettsia associated with human infections, was predominant among the PCR-positive samples. In 9 (0.8%) of the ticks, the partial sequences of 17kDa and ompB genes showed the greatest similarity to Rickettsia monacensis, an etiologic agent of Mediterranean spotted fever-like illness, previously described in southern Europe as well as to the Rickettsia sp.IrITA3 strain. For 15 (1.4%) of the ticks, the 17kDa, ompB, gltA and ompA genes showed the greatest similarity to Rickettsia sp. strain Davousti, Rickettsia japonica and Rickettsia heilongjiangensis, all closely phylogenetically related, the former previously found in Amblyomma tholloni ticks in Africa and previously not detected in Ixodes spp. ticks. The infestation prevalence of ticks infected with rickettsial organisms was four times higher among ground foraging birds than among other bird species, but the two groups were equally competent in transmitting Rickettsia species. The birds did not seem to serve as reservoir hosts for Rickettsia spp., but in one case it seems likely that the bird was rickettsiemic and that the ticks had acquired the bacteria from the blood of the bird. In conclusion, migratory passerine birds host epidemiologically important vector ticks and Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents and their diseases.

  • 349.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Framgångsrik utveckling av cellkulturodlat H5N1-influensa-vaccin stärker den globala beredskapen.2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, no 105, p. 2760-Article in journal (Refereed)
  • 350.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human antibody responses to hantavirus recombinant proteins & development of diagnostic methods1996Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Rodent-borne hantaviruses (family Bunyaviridae) cause two distinct human infections; hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). HFRS is a common viral zoonosis, characterized by fever, renal dysfunction and hemostatic imbalance. Four HFRS-associated hantaviruses have been described: Hantaan virus and Seoul virus mainly found in Asia, Dobrava virus, encountered in the Balkan region and Puumala virus (PUU), causing mild HFRS (nephropathia epidemica; NE) in Europe. HPS, recently discovered in the Americas, involves adult respiratory distress syndrome with a high mortality rate and is caused by Sin Nombre virus. Hantaviruses are enveloped and carry a RNA genome which encodes a polymerase, two glycoproteins and a nucleocapsid protein. The latter elicits a strong humoral immune response in infected patients.

    The clinical diagnosis of hantavirus infections has until recently relied on serological confirmation by immunofluorescense assay (IFA) and enzyme-linked immunosorbent assay (ELISA) using cell culture derived viral antigens. Due to the hazardous nature of hantaviruses and variable virus yield in cell culture we aimed at using recombinant hantavirus proteins for serological purposes.

    We expressed PUU N in E. coli (PUU rN) and found that high levels of IgM to this protein could be detected at onset of NE. This indicated that it was useful as the sole antigen for serodiagnosis. Our finding was confirmed by comparing IFA and PUU rN ELISA using 618 sera collected at the regional diagnostic laboratory.

    Full-length PUU rN is difficult to purify due to aggregation to E. coli remnants. We therefore located the important domain for the humoral immune response by utilizing truncated PUU rN proteins to its amino-terminal region (amino acid 7-94). Amino acid 1-117 of N of the five major human hantavirus pathogens were produced in E. coli. Serological assays based on them could detect IgM and IgG serum responses in 380 HFRS and HPS patients from Sweden, Finland, Slovenia, China, Korea and the USA with high sensitivity.

    In an epidemiological investigation of hantavirus serum responses in European Russia we unexpectedly found antibody responses to the hantaviruses found in east Asia and the Balkan region in 1.5 %, speaking in favour for the presence of such virus in this region.

    The degree of cross reactivity within the hantavirus genus was adressed by following the serum responses in NE patients. We found an increase of cross reactivity during the maturation of the immune response from onset of disease up to three years by comparing the IgG reactivity towards the hantavirus aminoterminal rN proteins.

    The first human isolate of the causative agent of NE in Scandinavia was recovered in cell culture from phytohemagglutinin stimulated leukocytes. Serological analysis revealed that this virus belongs to the PUU hantavirus serotype, distinct from the rodent prototype PUU Sotkamo. The human PUU Umeå is unique but genetically similar to rodent isolates from northern Sweden.

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