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  • 51.
    Björkman, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Finns det ett samband mellan självkänsla och sexuell risk hos svenska universitetsstudenter?: Självkänsla och stress inverkan på benägenheten att ha oskyddat sex - en populationsstudie i enkätform2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 52. Björkström, Niklas K
    et al.
    Lindgren, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Stoltz, Malin
    Fauriat, Cyril
    Braun, Monika
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Michaëlsson, Jakob
    Malmberg, Karl-Johan
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ljunggren, Hans-Gustaf
    Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus2011In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, no 1, p. 13-21Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

  • 53.
    Björkstén, Bengt
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    The nitroblue tetrazolium (NBT) test: a methodological and clinical study1974Doctoral thesis, comprehensive summary (Other academic)
  • 54. Björndal, Asa Szekely
    et al.
    Szekely, Laszlo
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ebola virus infection inversely correlates with the overall expression levels of promyelocytic leukaemia (PML) protein in cultured cells2003In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 3, p. 6-Article in journal (Refereed)
    Abstract [en]

    We have established a simple fixation and immunofluorescence staining procedure that allows specific co-detection and precise sub-cellular localization of the PML nuclear bodies and the Ebola virus encoded proteins NP, VP35 and VP40 in formaldehyde treated cells. Interferon-alpha treatment delays virus production in vitro. Intact PML bodies may play an anti-viral role in Ebola infected cells.

  • 55. Blusch, Jürgen H
    et al.
    Deryckere, François
    Windheim, Mark
    Ruzsics, Zsolt
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Adrian, Thomas
    Burgert, Hans-Gerhard
    The novel early region 3 protein E3/49K is specifically expressed by adenoviruses of subgenus D: implications for epidemic keratoconjunctivitis and adenovirus evolution2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 296, no 1, p. 94-106Article in journal (Refereed)
    Abstract [en]

    The early transcription unit 3 (E3) of adenoviruses (Ads) encodes immunomodulatory functions. We previously described a novel gene of 49K within the E3 region of Ad19a, an Ad of subgenus D that is similar to Ad8 and Ad37 causes epidemic keratoconjunctivitis (EKC). Interestingly, 49K was reported not to be present in Ad9 and Ad17, other subgenus D Ads not causing EKC. Therefore, we investigated whether 49K is selectively expressed in EKC-causing Ads. Using specific DNA probes, we detect 49K-homologous genes in all subgenus D Ads tested. Moreover, 49K-specific antibodies recognize a high molecular weight protein in cells infected with all subgenus D serotypes irrespective of their ability to cause EKC. Sequencing of several 49K genes reveals a high homology without a distinct feature recognizable for those of EKC-associated Ad strains. Thus, E3/49K is a subgenus D specific E3 protein whose expression does not correlate with the EKC-causing phenotype and thus may rather be implicated in illnesses commonly caused by this subgenus. Interestingly, the 49K sequences of Ad19a and Ad37 are identical. To estimate the extent of the sequence identity between these two viruses, we initially sequenced the right ITR and the hexon. This analysis revealed that the right ITR of Ad19a is identical to Ad37, while the hexon sequence is Ad19p-like. This suggested that the region of identity is much larger and that Ad19a arose by recombination of Ad37 with an Ad19p-like Ad. Further sequencing mapped the crossover within the DNA binding protein. Thus, Ad19a contains a large sequence block ( approximately 13 kb), from the 100K gene to the right ITR, identical to Ad37. The implications of these findings in light of the temporal appearance of the EKC-causing Ad strains are discussed.

  • 56.
    Bodén, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human papilloma virus: association with vulvovaginitis and genital intra-epithelial neoplasia1991Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In many women with gynecological complaints such as itching, burning, discharge, and fissures causing dyspareunia, examination of the vulvovaginal mucosa reveals hyperkeratotic and papillomatous changes. Polymerase Chain Reaction (PCR) technique revealed 64% of such lesions to harbour Human Papilloma Virus (HPV)- DNA, whereas Southern blot (SB) technique showed 50% to be positive for HPV- DNA.

    Women with papillomatous lesions were more often HPV-DNA positive than those with/Zat hyperkeratotic lesions. The virus-induced vulvovaginitis described was sometimes the sole cause of atypical Pap-smears. However, papilloma virus infections in vulva and vagina were often accompanied by cervical as well as vaginal and vulval intra-epithelial neoplasia.

    In women with an atypical Pap-smear, signs of HPV were observed by colposcopy in 58% of cases, by cytology in 21%, by histopathology in 53% and by HPV- DNA hybridization techniques in 46%. Colposcopy, cytology and histopathology were more sensitive than SB and Filter In Situ Hybridization (FISH) in detecting HPV in benign epithelium and in mild to moderate dysplasia. The FISH technique, when applied to cell samples and the SB technique for biopsy material proved equally sensitive when benign tissue and mild to moderate dysplasia were analysed. However, in women with severe dysplastic lesions, use of the SB technique on biopsy material proved more sensitive than FISH.

    In lesions with severe dysplasia, HPV-DNA was very often present (67% of CIN III lesions). HPV 16, which is capable of oncogenic transformation, was found in 54% of such tissue.

    At follow-up after laser treatment of genital intra-epithelial neoplasia, HPV-DNA could be detected in 38% of cases. This indicates that HPV may affect the entire mucosa of the lower genital tract, even when not clinically detectable. Thus, to eradicate the virus, systemic therapy would appear to be required.

    Vulvovaginal HPV infection is an entity with characteristic symptoms, morphological changes and oncogenic potential. Certain HPV-types are associated with the development of genital intra-epithelial neoplasia. The diagnostic methods presently available are not, however, sensitive enough for detection of HPV-infection and there is no effective treatment currently available. It would therefore be premature to suggest the introduction of a screening program for certain oncogenic HPV- types. Further study of the natural history of the virus infection is needed before any step can be taken toward using HPV screening in the effort to prevent cervical cancer.7

  • 57. Bofill-Mas, Silvia
    et al.
    Albinana-Gimenez, Nestor
    Clemente-Casares, Pilar
    Hundesa, Ayalkibet
    Rodriguez-Manzano, Jesus
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Calvo, Miquel
    Girones, Rosina
    Quantification and stability of human adenoviruses and polyomavirus JCPyV in wastewater matrices.2006In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 72, no 12, p. 7894-6Article in journal (Refereed)
    Abstract [en]

    Human adenoviruses (HAdV) and human polyomavirus JCPyV have been previously proposed as indicators of fecal viral contamination in the environment. Different wastewater matrices have been analyzed by applying real-time quantitative PCR procedures for the presence, quantity, and stability of a wide diversity of excreted HAdV and JCPyV. High quantities of HAdV and JCPyV were detected in sewage, effluent wastewater, sludge, and biosolid samples. Both viruses showed high stability in urban sewage. These results confirm the suitability of both viruses as indicators of human fecal viral pollution.

  • 58.
    Boman, Jens
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Gaydos, Charlotte
    Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Quinn, Thomas C
    Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
    Failure to detect Chlamydia trachomatis in cell culture by using a monoclonal antibody directed against the major outer membrane protein1997In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 35, no 10, p. 2679-2680Article in journal (Refereed)
    Abstract [en]

    Two commercially available monoclonal antibodies for cell culture confirmation of Chlamydia trachomatis were compared in two prospective studies and one large retrospective study. In total, more than 33,000 genital specimens were cultured in parallel and stained with both antibodies, one of which was directed against the major outer membrane protein (MOMP) and one uf which was directed against the lipopolysaccharide (LPS). We found the anti-LPS-based assay to be more sensitive and as specific as the anti-MOMP-based assay for C. trachomatis cell culture confirmation of genital specimens.

  • 59.
    Braml, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lactoferricin Mediated Infection of Adenovirus 52019Independent thesis Basic level (degree of Bachelor), 20 credits / 30 HE creditsStudent thesis
  • 60. Brion, G
    et al.
    Lingeriddy, S
    Neelakantan, T R
    Wang, M
    Girones, R
    Lees, D
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Vantarakis, A
    Probing Norwalk-like virus presence in shellfish, using artificial neural networks.2004In: Water Science and Technology, ISSN 0273-1223, E-ISSN 1996-9732, Vol. 50, no 1, p. 125-9Article in journal (Refereed)
    Abstract [en]

    A database was examined using artificial neural network (ANN) models to investigate the efficacy of predicting PCR-identified Norwalk-like virus presence and absence in shellfish. The relative importance of variables in the model and the predictive power obtained by application of ANN modelling methods were compared with previously developed logistic regression models. In addition, two country-specific datasets were analysed separately with ANN models to determine if the relative importance of the input variables was similar for geographically diverse regions. The results of this analysis found that ANN models predicted Norwalk-like virus presence and absence in shellfish with equivalent, and better, precision than logistic regression models. For overall classification performance, ANN modelling had a rate of 93%, vs 75% for the logistic regression. ANN models were able to illuminate the site-specific relationships between indicators and pathogens.

  • 61. Brion, Gail
    et al.
    Viswanathan, Chandramouli
    Neelakantan, T R
    Lingireddy, Srinivasa
    Girones, Rosina
    Lees, David
    Allard, Annika
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Vantarakis, Apostolos
    Artificial neural network prediction of viruses in shellfish.2005In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 71, no 9, p. 5244-53Article in journal (Refereed)
    Abstract [en]

    A database was probed with artificial neural network (ANN) and multivariate logistic regression (MLR) models to investigate the efficacy of predicting PCR-identified human adenovirus (ADV), Norwalk-like virus (NLV), and enterovirus (EV) presence or absence in shellfish harvested from diverse countries in Europe (Spain, Sweden, Greece, and the United Kingdom). The relative importance of numerical and heuristic input variables to the ANN model for each country and for the combined data was analyzed with a newly defined relative strength effect, which illuminated the importance of bacteriophages as potential viral indicators. The results of this analysis showed that ANN models predicted all types of viral presence and absence in shellfish with better precision than MLR models for a multicountry database. For overall presence/absence classification accuracy, ANN modeling had a performance rate of 95.9%, 98.9%, and 95.7% versus 60.5%, 75.0%, and 64.6% for the MLR for ADV, NLV, and EV, respectively. The selectivity (prediction of viral negatives) was greater than the sensitivity (prediction of viral positives) for both models and with all virus types, with the ANN model performing with greater sensitivity than the MLR. ANN models were able to illuminate site-specific relationships between microbial indicators chosen as model inputs and human virus presence. A validation study on ADV demonstrated that the MLR and ANN models differed in sensitivity and selectivity, with the ANN model correctly identifying ADV presence with greater precision.

  • 62. Bruening, Janina
    et al.
    Lasswitz, Lisa
    Banse, Pia
    Kahl, Sina
    Marinach, Carine
    Vondran, Florian W.
    Kaderali, Lars
    Silvie, Olivier
    Pietschmann, Thomas
    Meissner, Felix
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB2018In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, no 7, article id e1007111Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.

  • 63. Bucht, Göran
    et al.
    Sjölander, Katarina Brus
    Eriksson, Solveig
    Lindgren, Lena
    Lundkvist, Åke
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Modifying the cellular transport of DNA-based vaccines alters the immune response to hantavirus nucleocapsid protein2001In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 19, no 28-29, p. 3820-3829Article in journal (Refereed)
    Abstract [en]

    Puumala virus is a member of the hantavirus genus (family Bunyaviridae) and is one of the causative agents of hemorrhagic fever with renal syndrome (HFRS) in Europe. A genetic vaccination approach was conducted to investigate if the immune response could be modulated using different cellular secretion and/or localisation signals, and the immune responses were analysed in BALB/c mice and in a bank vole infectious model. Rodents vaccinated with DNA constructs encoding the antigen fused to an amino-terminal secretion signal raised significantly higher antibody levels when compared to using constructs lacking secretion signals. Furthermore, the ratios of the IgG subclasses (IgG2a/IgG1) were raised by the use of cellular localisation signals, indicating a more pronounced Th1-type of immune response. The majority of the mice, or bank voles, immunised with DNA encoding a secreted form of the antigen showed a positive lymphoproliferative response and were protected against challenge with Puumala virus (strain Kazan-wt).

  • 64. Burmeister, Wim P
    et al.
    Guilligay, Delphine
    Cusack, Stephen
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Crystal structure of species D adenovirus fiber knobs and their sialic acid binding sites2004In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 78, no 14, p. 7727-7736Article in journal (Refereed)
    Abstract [en]

    Adenovirus serotype 37 (Ad37) belongs to species D and can cause epidemic keratoconjunctivitis, whereas the closely related Ad19p does not. Primary cell attachment by adenoviruses is mediated through receptor binding of the knob domain of the fiber protein. The knobs of Ad37 and Ad19p differ at only two positions, Lys240Glu and Asn340Asp. We report the high-resolution crystal structures of the Ad37 and Ad19p knobs, both native and in complex with sialic acid, which has been proposed as a receptor for Ad37. Overall, the Ad37 and Ad19p knobs are very similar to previously reported knob structures, especially to that of Ad5, which binds the coxsackievirus-adenovirus receptor (CAR). Ad37 and Ad19p knobs are structurally identical with the exception of the changed side chains and are structurally most similar to CAR-binding knobs (e.g., that of Ad5) rather than non-CAR-binding knobs (e.g., that of Ad3). The two mutations in Ad19p result in a partial loss of the exceptionally high positive surface charge of the Ad37 knob but do not affect sialic acid binding. This site is located on the top of the trimer and binds both alpha(2,3) and alpha(2,6)-linked sialyl-lactose, although only the sialic acid residue makes direct contact. Amino acid alignment suggests that the sialic acid binding site is conserved in several species D serotypes. Our results show that the altered viral tropism and cell binding of Ad19p relative to those of Ad37 are not explained by a different binding ability toward sialyl-lactose.

  • 65.
    Bylund, Göran O
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nord, Stefan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lövgren, J Mattias
    Wikström, P Mikael
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Alterations in the β flap and β' dock domains of the RNA polymerase abolish NusA-mediated feedback regulation of the metY-nusA-infB operon2011In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 193, no 16, p. 4113-4122Article in journal (Refereed)
    Abstract [en]

    The RimM protein in Escherichia coli is important for the in vivo maturation of 30S ribosomal subunits and a ΔrimM mutant grows poorly due to assembly and translational defects. These deficiencies are suppressed partially by mutations that increase the synthesis of another assembly protein, RbfA, encoded by the metY-nusA-infB operon. Among these suppressors are mutations in nusA that impair the NusA-mediated negative-feedback regulation at internal intrinsic transcriptional terminators of the metY-nusA-infB operon. We describe here the isolation of two new mutations, one in rpoB and one in rpoC (encoding the β and β' subunits of the RNA polymerase, respectively), that increase the synthesis of RbfA by preventing NusA from stimulating termination at the internal intrinsic transcriptional terminators of the metY-nusA-infB operon. The rpoB2063 mutation changed the isoleucine in position 905 of the β flap-tip helix to a serine, while the rpoC2064 mutation duplicated positions 415 to 416 (valine-isoleucine) at the base of the β' dock domain. These findings support previously published in vitro results, which have suggested that the β flap-tip helix and β' dock domain at either side of the RNA exit tunnel mediate the binding to NusA during transcriptional pausing and termination.

  • 66.
    Bystrom, Julia Wigren
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Näslund, Jonas
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Trulsson, Fredrik
    Umeå University, Faculty of Science and Technology, European CBRNE Center. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wesula Lwande, Olivia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Bucht, Göran
    Umeå University, Faculty of Science and Technology, European CBRNE Center.
    Quantification and kinetics of viral RNA transcripts produced in Orthohantavirus infected cells2018In: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 15, p. 1-7, article id 18Article in journal (Refereed)
    Abstract [en]

    Background: Rodent borne viruses of the Orthohantavirus genus cause hemorrhagic fever with renal syndrome among people in Eurasia, and hantavirus cardiopulmonary syndrome in the Americas. At present, there are no specific treatments or efficient vaccines against these diseases. Improved understanding of viral transcription and replication may instigate targeted treatment of Orthohantavirus infections. For this purpose, we investigated the kinetics and levels of viral RNA transcription during an ongoing infection in-vitro. Methods: Vero E6 cells were infected with Puumala Orthohantavirus (strain Kazan) before cells and supernatants were collected at different time points post infection for the detection of viral RNAs. A plasmid containing primer binding sites of the three Orthohantavirus segments small (S), medium (M) and large (L) was constructed and standard curves were generated to calculate the copy numbers of the individual transcripts in the collected samples. Results: Our results indicated a rapid increase in the copy number of viral RNAs after 9 h post infection. At peak days, 2-6 days after infection, the S- and M-segment transcripts became thousand and hundred-fold more abundant than the copy number of the L-segment RNA, respectively. The presence of viral RNA in the cell culture media was detected at later time-points. Conclusions: We have developed a method to follow RNA transcription in-vitro after synchronous infection of Vero cells. The obtained results may contribute to the understanding of the viral replication, and may have implications in the development of antiviral drugs targeting transcription or replication of negative stranded RNA viruses.

  • 67.
    Börjesson, Sara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Självkänsla och sexuellt risktagande - en enkätstudie hos sökande på STD-mottagning2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 68.
    Caraballo, Rémi
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bauer, Johannes
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Liaci, Antonio-Manuel
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Storm, Rickard J
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Qian, Weixing
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stehle, Thilo
    Interfaculty Institute of Biochemistry, University of Tübingen, Germany ; Department of Pediatrics, Vanderbilt University School of Medicine, USA.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 35, p. 9194-9205Article in journal (Refereed)
    Abstract [en]

    Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.

  • 69.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Gärdén, Bodil
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    [Contact tracing a year back is worthwhile. Follow the Vasterbottens example to prevent Chlamydia transmission in Sweden!]2005In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 102, no 7, p. 468-71Article in journal (Refereed)
    Abstract [sv]

    Contact tracing is proved to be a good way to prevent asymptomatic sexually transmitted infections, such as Chlamydia trachomatis, from spreading. According to the Swedish law a physician has to report all cases of genital C. trachomatis to the County Medical Officer of Health and to the National institute for Infectious Disease Control and perform contact tracing. An evaluation of the sexual history 6 months back in time is recommended and standard in most of the country. The county of Västerbotten has one of the lowest incidenses of C. trachomatis in Sweden though the population is younger than the Swedish average. During year 2002 the contact tracing in Västerbotten was evaluated by sending a questionnaire to everyone who reported a case of genital C. trachomatis. We recived 534 (98%) out of 544 questionnaires. The patients reported 1360 partners, 2.5 on average, 1129 were identified. 761 had a known test result and 497 of them were positive, 0.9 on average. 72% of the contact tracers evaluated the sexual history > or = 12 months back in time. 78% of the contact tracings were performed by four social workers. Their patients reported 2.5 partners on average and 80% evaluated > or = 12 months back in time. 14 persons did only one contact tracing, 1.3 partners/index on average, 40% evaluated > or = 12 months back in time. 82% of the partners had sex with the infected patient 0-6 months before the patients was diagnosed with C. trachomatis, 75% out of those with a known test result were infected, 16% had sex 7-12 months before diagnosis, 30% infected. (The C. trachomatis prevalence in Sweden is estimated to be 2.7-4.9% among young women.) Conclusion: A few experienced persons tracing for at least 12 month back in time is probably two important reasons why Västerbotten has such a small C. trachomatis incidence.

  • 70.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Österlund, A
    Communicable Disease Prevention and Control, Sunderby Hospital, Luleå, Sweden.
    Gärdén, B
    The School of Life Sciences, University of Skövde, Skövde, Sweden.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Improved contact tracing for Chlamydia trachomatis with experienced tracers, tracing for one year back in time and interviewing by phone in remote areas2008In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 84, no 3, p. 239-242Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate the Swedish model for contact tracing and especially the "Västerbotten model" with centralised, extended contact interview periods, sometimes by telephone.

    METHODS: Using questionnaires, the contact tracing and interview procedure was evaluated during 2002, followed by an evaluation of contact interviewing by phone in 2005-6.

    RESULTS: Patients with diagnosed Chlamydia trachomatis infection reported on average 2.5 sexual contacts, 3.0 contacts when contact interviewing was performed at the clinic, and 2.3 contacts when performed by phone. 65% of the sexual contacts with a known test result were infected.

    CONCLUSION: Centralised contact tracing, exploring the sexual history for at least 12 months back in time, shows good results. Combined with screening of certain risk groups it is probably one effective way of preventing C trachomatis infections. Preventing C trachomatis by primary prevention such as information and counselling is, however, still of great importance.

  • 71.
    Carré, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Edman, Anne-Christine
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Chlamydia trachomatis in the throat: is testing necessary?2008In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, ISSN ISSN 0001-5555, EISSN 1651-2057, Vol. 88, no 2, p. 187-188Article in journal (Refereed)
  • 72. Chen, Tianhui
    et al.
    Lukanova, Annekatrin
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schock, Helena
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    IGF-I during primiparous pregnancy and maternal risk of breast cancer2010In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 121, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer.

  • 73. Chen, Tianhui
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Afanasyeva, Yelena
    Schock, Helena
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lukanova, Annekatrin
    Maternal hormones during early pregnancy: a cross-sectional study2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 5, p. 719-727Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

  • 74. Chepurnov, A A
    et al.
    Fedosova, N I
    Egoricheva, I N
    Poltavchenko, A G
    Elgh, F
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    [Development of a method for rapid detection of Ebola virus antibodies and antigen]2007In: Voprosy virusologii, ISSN 0507-4088, Vol. 52, no 3, p. 41-3Article in journal (Other academic)
  • 75.
    Chitheer, Athir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Generation of a Chimeric HAdV-5/56 Virus2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 76. Chu, Y K
    et al.
    Jennings, G
    Schmaljohn, A
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hjelle, B
    Lee, H W
    Jenison, S
    Ksiazek, T
    Peters, C J
    Rollin, P
    Cross-neutralization of hantaviruses with immune sera from experimentally infected animals and from hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome patients.1995In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 172, no 6, p. 1581-4Article in journal (Refereed)
    Abstract [en]

    Plaque-reduction neutralization tests were done with eight of nine known representative hantaviruses and immune sera from experimentally infected animals and from patients with hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Results obtained with animal sera demonstrated each virus to be antigenically unique. Neutralization with the HPS patient sera was highest with Sin Nombre (SN) virus and to a lesser extent with Black Creek Canal (BCC) virus. Sera from Korean HFRS patients reacted best with Hantaan virus, but cross-reactivity with all other viruses except Thottapalayam (TPM) virus was also observed. Sera from Swedish HFRS patients reacted best with Puumala virus but cross-reacted with Prospect Hill, SN, and BCC viruses and to a lesser extent with all of the other viruses except TPM virus.

  • 77.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hammargren, Edvin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Whitaker, Heather
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Klingstrom, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Increased Risk of Acute Myocardial Infarction and Stroke During Hemorrhagic Fever With Renal Syndrome A Self-Controlled Case Series Study2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 129, no 12, p. 1295-1302Article in journal (Refereed)
    Abstract [en]

    Background We recently observed that cardiovascular causes of death are common in patients with hemorrhagic fever with renal syndrome (HFRS), which is caused by hantaviruses. However, it is not known whether HFRS is a risk factor for the acute cardiovascular events of acute myocardial infarction (AMI) and stroke. Methods and Results Personal identification numbers from the Swedish HFRS patient database (1997-2012; n=6643) were cross-linked with the National Patient Register from 1987 to 2011. Using the self-controlled case series method, we calculated the incidence rate ratio of AMI/stroke in the 21 days after HFRS against 2 different control periods either excluding (analysis 1) or including (analysis 2) fatal AMI/stroke events. The incidence rate ratios for analyses 1 and 2 for all AMI events were 5.53 (95% confidence interval [CI], 2.6-11.8) and 6.02 (95% CI, 2.95-12.3) and for first AMI events were 3.53 (95% CI, 1.25-9.96) and 4.64 (95% CI, 1.83-11.77). The incidence rate ratios for analyses 1 and 2 for all stroke events were 12.93 (95% CI, 5.62-29.74) and 15.16 (95% CI, 7.21-31.87) and for first stroke events were 14.54 (95% CI, 5.87-36.04) and 17.09 (95% CI, 7.49-38.96). The majority of stroke events occurred in the first week after HFRS. Seasonal effects were not observed, and apart from 1 study, neither sex nor age interacted with the associations observed in this study. Conclusions There is a significantly increased risk for AMI and stroke in the immediate time period after HFRS. Therefore, HFRS patients should be carefully monitored during the acute phase of disease to ensure early recognition of symptoms of impending AMI or stroke.

  • 78.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sundberg, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Dunne, Eimear
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Kenny, Dermot
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 79. Cupelli, Karolina
    et al.
    Müller, Steffen
    Persson, David B
    Jost, Marco
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Stehle, Thilo
    Structure of adenovirus type 21 knob in complex with CD46 reveals key differences in receptor contacts among species B adenoviruses2010In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 84, no 7, p. 3189-3200Article in journal (Refereed)
    Abstract [en]

    The complement regulation protein CD46 is the primary attachment receptor for most species B adenoviruses (Ads). However, significant variability exists in sequence and structure among species B Ads in the CD46-binding regions, correlating with differences in affinity. Here, we report a structure-function analysis of the interaction of the species B Ad21 knob with the two N-terminal repeats SCR1 and SCR2 of CD46, CD46-D2. We have determined the structures of the Ad21 knob in its unliganded form as well as in complex with CD46-D2, and we compare the interactions with those observed for the Ad11 knob-CD46-D2 complex. Surface plasmon resonance measurements demonstrate that the affinity of Ad21 knobs for CD46-D2 is 22-fold lower than that of the Ad11 knob. The superposition of the Ad21 and Ad11 knob structures in complex with CD46-D2 reveals a substantially different binding mode, providing an explanation for the weaker binding affinity of the Ad21 knob for its receptor. A critical difference in both complex structures is that a key interaction point, the DG loop, protrudes more in the Ad21 knob than in the Ad11 knob. Therefore, the protruding DG loop does not allow CD46-D2 to approach the core of the Ad21 knob as closely as in the Ad11 knob-CD46-D2 complex. In addition, the engagement of CD46-D2 induces a conformational change in the DG loop in the Ad21 knob but not in the Ad11 knob. Our results contribute to a more profound understanding of the CD46-binding mechanism of species B Ads and have relevance for the design of more efficient gene delivery vectors.

  • 80.
    Dahlquist, Gisela G
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Forsberg, Jenny
    Hagenfeldt, Lars
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Increased prevalence of enteroviral RNA in blood spots from newborn children who later developed type 1 diabetes: a population-based case-control study.2004In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 27, no 1, p. 285-6Article in journal (Refereed)
  • 81. Dahlström, Lisen Arnheim
    et al.
    Andersson, Kristin
    Luostarinen, Tapio
    Thoresen, Steinar
    Ögmundsdottir, Helga
    Tryggvadottir, Laufey
    Wiklund, Fredrik
    Skare, Gry B
    Eklund, Carina
    Sjölin, Kia
    Jellum, Egil
    Koskela, Pentti
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lehtinen, Matti
    Dillner, Joakim
    Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 12, p. 2541-2550Article in journal (Refereed)
    Abstract [en]

    Background: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects.

    Methods: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI.

    Results: Exposure to HPV16 was the strongest risk factor for cervical cancer [ OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3).

    Conclusions: A large prospective study has assessed the role of different STIs in cervical cancer.

    Impact: Prospective evidence supports cofactor role of some STI in cervical cancer.

    Cancer Epidemiol Biomarkers Prev; 20(12); 2541-50. (C) 2011 AACR.

  • 82. Davidsson, Sabina
    et al.
    Söderquist, Bo
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Andrén, Ove
    Unemo, Magnus
    Mölling, Paula
    Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin2012In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed)
    Abstract [en]

    Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology. The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences. The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types. Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

  • 83. de Diego, J L
    et al.
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Zychlinsky, A
    Sensing, presenting, and regulating PAMPs.2007In: Ernst Schering Foundation symposium proceedings, no 3, p. 83-95Article in journal (Refereed)
    Abstract [en]

    Recognition of microbial infection and initiation of immune responses are controlled by multiple mechanisms. Toll-like receptors (TLRs) are key components of the innate immune system that detect microbial infection. TLR activation helps to eliminate the invading pathogens, coordinate systemic defenses, and initiate adaptive immune responses. Despite progress elucidating the TLR signaling aspects and the physiological relevance of TLRs in microbial infections, the molecular basis of microbial recognition by TLRs is still not fully understood. In this article we focus on the availability of microbial ligands to regulate presentation to TLRs and assist in our understanding of TLR-mediated microbial recognition.

  • 84. 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.

  • 85. 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.

  • 86.
    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.

  • 87.
    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.

  • 88.
    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)
  • 89. 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.

  • 90.
    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.

  • 91.
    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
  • 92.
    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)
  • 93.
    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.

  • 94.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Influensapandemiers påverkan på samhället; nödvändig erfarenhetsbakgrund för pandemiplanering2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 8, no 104, p. 614-619Article in journal (Refereed)
  • 95.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    [The effect of pandemics on society. Historical experience necessary for today's preparedness]2007In: Lakartidningen, ISSN 0023-7205, Vol. 104, no 8, p. 615-9Article in journal (Other academic)
  • 96.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Linderholm, M
    Evaluation of six commercially available kits using purified heterophile antigen for the rapid diagnosis of infectious mononucleosis compared with Epstein-Barr virus-specific serology.1996In: Clinical and Diagnostic Virology, ISSN 0928-0197, E-ISSN 1873-4901, Vol. 7, no 1, p. 17-21Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Novel commercial kits based on antibody reactivity to purified heterophile antigens have recently been introduced for the diagnosis of Epstein-Barr (EB) virus-associated infectious mononucleosis (IM). It is important to determine possible improvements in the performance and reliability of such tests for the diagnosis of IM.

    OBJECTIVE: To evaluate the reliability of six commercially available kits for the rapid diagnosis of IM in comparison to EB-virus-specific serology.

    STUDY DESIGN: In total, 100 sera, 53 from patients with serologically verified primary EB virus infection and 47 from EB-virus-immune or -susceptible patients, were used to evaluate the six rapid test kits: Monolatex, Mono-Latex, Mono-Lex (latex agglutination-based kits), Mono-Plus, IM-Check and Clearview IM (solid-phase-based kits). EB-virus-specific serologies including detection of viral capsid antigen IgM and IgG and EB nuclear antigen-1 IgG, were used as reference methods.

    RESULTS: Compared with the reference methods, the sensitivities and specificities of the heterophile antibody test kits were 70-92% and 96-100%, respectively. IM-Check had a low sensitivity and was difficult to read. The remaining kits performed well.

    CONCLUSION: Monolatex, Mono-Latex, Mono-Lex, Mono-Plus and Clearview IM can be recommended for the confirmation of EB-virus-associated infectious mononucleosis. Clearview IM combined a high sensitivity and specificity with very simple one-step solid-phase-based procedure.

  • 97.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Linderholm, M
    Wadell, G
    Juto, P
    The clinical usefulness of a Puumalavirus recombinant nucleocapsid protein based enzyme-linked immunosorbent assay in the diagnosis of nephropathia epidemica as compared with an immunofluorescence assay.1996In: Clinical and Diagnostic Virology, ISSN 0928-0197, E-ISSN 1873-4901, Vol. 6, no 1, p. 17-26Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nephropathia epidemica (NE), a hemorrhagic fever with renal syndrome (HFRS) predominantly encountered in northern Europe, is a febrile disease, commonly associated with acute renal impairment. A rapid and reliable serological diagnosis is required to differentiate NE from other acute febrile illnesses in endemic areas.

    OBJECTIVE: To evaluate a Puumala (PUU) virus recombinant nucleocapsid protein (rN) based enzyme-linked immunosorbent assay (ELISA) for the serological diagnosis of NE as compared with an immunofluorescence assay (IFA) in a clinically relevant patient sample.

    STUDY DESIGN: During a four-month period, 618 serum samples from 512 patients with an illness suggestive of NE, sent to the Department of Clinical Virology for serological analysis, were included in the study. All sera were tested by PUU rN ELISA for presence of specific IgG, IgM and IgA antibodies and by IFA using PUU virus infected cells as antigen for presence of IgG and IgM antibodies. Patients with discordant results by IFA and rN ELISA were further serologically and/or clinically evaluated to assess the probability of NE.

    RESULTS: Compared to IFA, the specificities of the IgM and IgG rN ELISA were 100% and the corresponding sensitivities were 94.0%. The positive and negative predictive values of the PUU IgM rN ELISA in diagnosing NE infection was 100 and 98.6%, respectively. The positive predictive values for present NE infection of IgG rN ELISA and IFA were 68.3 and 71.4%, respectively. The positive predictive value of IgA rN ELISA was 95.8% and the negative 92.7%.

    CONCLUSIONS: The demonstration of specific IgM by rN ELISA is a highly specific and reliable method for the serological confirmation of NE. Detection of IgG antibodies by rN ELISA or IFA has a low predictive value to diagnose NE in an endemic area. The diagnostic value of IgA determination is in between IgM and IgG determinations.

  • 98.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Linderholm, M
    Wadell, G
    Tärnvik, A
    Juto, P
    Development of humoral cross-reactivity to the nucleocapsid protein of heterologous hantaviruses in nephropathia epidemica.1998In: FEMS Immunology and Medical Microbiology, ISSN 0928-8244, E-ISSN 1574-695X, Vol. 22, no 4, p. 309-15Article in journal (Refereed)
    Abstract [en]

    A hantavirus infection is followed by a prominent antibody response to the viral nucleocapsid protein. Antibodies from patients infected with one hantavirus cross-react to varying degrees with the nucleocapsid protein of other viruses of the genus. We studied the cross-reactivity in serially obtained blood samples from 17 patients with nephropathia epidemica, a European form of hemorrhagic fever with renal syndrome caused by Puumala virus. Recombinant truncated nucleocapsid protein (aa 1-117) of Puumala virus and four other hantaviruses, Hantaan, Seoul, Dobrava and Sin Nombre viruses, were used as antigens in an indirect ELISA. In most patients, an IgG response to the Puumala virus derived recombinant protein was detected within 2-8 days of onset of disease, remained high for 2-5 months, and declined gradually within 2-3 years. All patients had IgG antibodies cross-reacting with the nucleocapsid protein of Sin Nombre virus. The ratio of the ELISA values obtained with Sin Nombre vs. Puumala virus protein as antigen increased with time after onset of disease. To a lesser extent, cross-reacting IgG antibodies also occurred to Hantaan, Seoul, and Dobrava virus antigens. In the acute phase of the disease, two patients showed IgG antibodies to one or more of these viruses whereas 2-5 months later, 11 of 16 patients had IgG antibodies to all three viruses. IgM and IgA responses to the nucleocapsid protein of Puumala virus were transitory and cross-reactivities were weak. In conclusion, after onset of nephropathia epidemica the IgG response to the Puumala virus nucleocapsid protein was associated with a gradually increasing cross-reactivity to the nucleocapsid protein of heterologous hantavirus. Our findings have implications for the interpretation of serological data, both in the diagnostics of nephropathia epidemica and in seroprevalence studies.

  • 99.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lundkvist, A
    Alexeyev, O A
    Stenlund, H
    Avsic-Zupanc, T
    Hjelle, B
    Lee, H W
    Smith, K J
    Vainionpää, R
    Wiger, D
    Wadell, G
    Juto, P
    Serological diagnosis of hantavirus infections by an enzyme-linked immunosorbent assay based on detection of immunoglobulin G and M responses to recombinant nucleocapsid proteins of five viral serotypes.1997In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 35, no 5, p. 1122-30Article in journal (Refereed)
    Abstract [en]

    Worldwide, hantaviruses cause more than 100,000 human infections annually. Rapid and accurate methods are important both in monitoring acute infections and for epidemiological studies. We and others have shown that the amino termini of hantavirus nucleocapsid proteins (Ns) are sensitive tools for the detection of specific antibodies in hantavirus disease. Accordingly, we expressed truncated Ns (amino acids 1 to 117) in Escherichia coli from the five hantaviruses known to be pathogenic to man; Hantaan (HTN), Seoul (SEO), Dobrava (DOB), Sin Nombre (SN), and Puumala (PUU) viruses. In order to obtain pure antigens for use in an enzyme-linked immunosorbent assay (ELISA), the recombinant proteins were purified by polyhistidine-metal chelate affinity chromatography. Polyclonal animal antisera and a panel of serum specimens from hantavirus-infected individuals from Scandinavia, Slovenia, Russia, Korea, China, and the United States were used to evaluate the usefulness of the method. With both human and animal sera, it was possible to designate the antibody response into two groups: those with HTN, SEO, and DOB virus reactivity on the one hand and those with SN and PUU virus reactivity on the other. In sera from Scandinavia, European Russia, and the United States, the antibody response was directed mainly to the PUU and SN virus group. The sera from Asia reacted almost exclusively with the HTN, SEO, and DOB types of viruses. This was true for both the immunoglobulin M (IgM) and IgG antibody responses, indicating that this type of discrimination can be done during the acute phase of hantavirus infections. Both the HTN, SEO, and DOB virus and the PUU and SN virus types of antibody response patterns were found in patients from the Balkan region (Solvenia).

  • 100.
    Elgh, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lundkvist, A
    Alexeyev, O A
    Wadell, G
    Juto, P
    A major antigenic domain for the human humoral response to Puumala virus nucleocapsid protein is located at the amino-terminus.1996In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 59, no 1-2, p. 161-72Article in journal (Refereed)
    Abstract [en]

    Nephropathia epidemica (NE), the major form of hemorrhagic fever with renal syndrome in Europe, is caused by the hantavirus serotype Puumala (PUU). The PUU virus nucleocapsid protein (N) has been shown to be highly immunogenic both in laboratory animals and in man. We aimed to locate domains important in humoral immune reactivity and to use this information to develop a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for serological diagnosis of NE. Escherichia coli poly-histidine fusion protein expression vectors containing over-lapping gene segments encoding the PUU virus N (PUU rN) were constructed. The resulting gene products were examined by immunoblots and ELISA with polyclonal and monoclonal antibodies. The dominating antigenic region of PUU rN was located between amino acids (aa) 7 and 94. A recombinant fusion protein containing aa 7-137 of PUU virus N (PUU rN delta 5) was used for the detection of specific IgG and IgM responses in NE. ELISA based on PUU rN delta 5 was found to have equal sensitivity and specificity as compared to the full length recombinant PUU rN by ELISA, for both acute serological diagnosis of NE and for seroepidemiological screening purposes. Furthermore, this protein is easier to handle than full length PUU rN due to its higher solubility in aqueous solutions.

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