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  • 251. Nordström, Henrik
    et al.
    Johansson, Patrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Li, Quan-Gen
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lundkvist, Ake
    Nilsson, Peter
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Microarray technology for identification and distinction of hantaviruses.2004In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 72, no 4, p. 646-655Article in journal (Refereed)
    Abstract [en]

    DNA microarrays combine high-precision technology with advanced molecular biology to achieve high-throughput screening of DNA fragments. In this study, we investigated the potential of the cDNA microarray technique to identify and discriminate PCR derived amplicons from genetically highly similar viruses. The wide range of sequence variation among hantaviruses makes them suitable as a model for this purpose. The hantaviruses, carried by rodents, cause several hundred thousand cases of severe human disease every year in many parts of the world. A hantavirus-specific microarray, including DNA fragments from 12 viral isolates of six different hantaviruses, was designed. The S and M genome segments were represented by 500-nucleotide overlapping and 250-nucleotide non-overlapping fragments. A considerable ability to distinguish between different hantaviruses was demonstrated using a novel analysis method. Even different isolates of a single virus, were identified correctly despite 90% sequence similarity. The distinction ability was accompanied by a tolerance for smaller sequence differences, which makes the microarray suitable for testing samples containing unknown viruses. Viral genetic material found in samples from the lungs of bank voles caught in the wild was identified precisely, which demonstrated further the potential for this technology.

  • 252.
    Nourmohammadi, Sema
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Time trends in the seroprevalence of herpesvirus in the Swedish population2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 253.
    Novak, Daniel P
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Edman, A-C
    Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Jonsson, Monica
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Karlsson, Roger B
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    The Internet, a simple and convinient tool in Chlamydia trachomatis screening of young people2003In: Eurosurveillance, ISSN 1025-496, Vol. 8, no 9, p. 171-176Article in journal (Refereed)
  • 254.
    Ny, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Enkvist, K
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Fredriksson, C
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Järvinen, S
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lund, B
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Isolation and characterization of the genomic region carrying the human tissue plasminogen activator gene1985In: Progress in Fibrinolysis. Vol. 7 / [ed] John Forsyth Davidsson, Churchill Livingstone , 1985, p. 205-207Chapter in book (Refereed)
  • 255.
    Ny, Tor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lund, B
    The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains.1984In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 81, no 17, p. 5355-9Article in journal (Refereed)
    Abstract [en]

    A genomic clone carrying the human tissue-type plasminogen activator (t-PA) gene was isolated from a cosmid library, and the gene structure was elucidated by restriction mapping, Southern blotting, and DNA sequencing. The cosmid contained all the coding parts of the mRNA, except for the first 58 bases in the 5' end of the mRNA, and had a total length of greater than 20 kilobases. It was separated into at least 14 exons by at least 13 introns, and the exons seemed to code for structural or functional domains. Thus, the signal peptide, the propeptide, and the domains of the heavy chain, including the regions homologous to growth factors, and to the "finger" structure of fibronectin, are all encoded by separate exons. In addition, the two kringle regions of t-PA were both coded for by two exons and were cleaved by introns at identical positions. The region coding for the light chain, comprising the serine protease part of the molecule was split by four introns, revealing a gene organization similar to other serine proteases.

  • 256.
    Nyberg, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mechanisms involved in adenovirus binding to and infection of host cells2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The adenovirus (Ad) family consists of 52 different human types, which are divided into seven species (A-G). Human Ads cause disease in the respiratory tract, lymphoid tissue, intestine, urinary tract, and/or in the eye. Most, but not all Ads have been demonstrated to use the coxsackie-adenovirus receptor (CAR) as an efficient receptor in vitro, but CAR has been questioned as an in vivo-receptor for various reasons. Thus, there are reasons to believe that Ads use other mechanisms for binding to target cells. In an attempt to investigate the impact of tear fluid during in vitro infection of ocular Ads (i.e. Ad37), using corneal cells, we found that human tear fluid promoted infection of an Ad with pronounced respiratory tropism (i.e. Ad5) used here as a control, but surprisingly not of Ad37. Furthermore using a virus overlay protein blotting assay we found that Ad5 bound to several tear fluid proteins. One of these, human lactoferrin (hLf) which is a component that belongs to the innate immune system in various body fluids, was alone able to promote both binding and infection of all species C Ads (Ad1, Ad2, Ad5, Ad6) in epithelial cells. hLf was also found to promote gene delivery (GFP) from an Ad5-based vector. Further we have identified lactoferricin (Lfcin), the N-terminal part of hLf, as to be responsible for this effect. We also show that plasma, saliva, and tear fluid promote infection of Ad5 in respiratory and ocular epithelial cells, and that plasma promotes infection of Ad31. The component in plasma that is responsible for this effect is likely to be coagulation factor IX (FIX) and X (FX), since both these factors were able to promote binding and infection of Ad5 and/or Ad31 in epithelial cells. Finally, we show that the excess of fiber production from initial Ad infection and the release of fibers before the particle itself is released caused masking of the tropism-specific receptors in both infected and non-infected surrounding cells. This means that the overproduction of fibers affects the ability of Ad to spread within tissues.

    We conclude that soluble components in body fluids, such as hLf, FIX, and FX have the ability to mediate binding and infection of selected human Ads (species C and Ad31) in epithelial cells that represent the tropism of these Ads. We suggest that these components may serve as bridges between the virion and the cell surface. This is contributes to the knowledge about Ad lifecycle, and might help to improve the de-/retargeting of gene therapy based on Ad vectors.

  • 257.
    Näslund, Jonas
    Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Clinical Microbiology, Virology.
    Rift Valley fever: development of diagnostics and vaccines2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rift Valley Fever virus (RVFV) causes an infection with severe impact on animal and human health. The disease is endemic throughout almost the entire African continent and large regions of the Arabian Peninsula. During epidemics, high mortality is observed in animals, especially among cattle, goats, and sheep. In humans, the symptoms vary from a benign influenza-like disease to a life-threatening hemorrhagic fever. Due to the devastating effect on communities in endemic regions and the possibility of further spread of this virus, there is an imperative need to improve and develop control measurements against this emerging disease. Therefore, this thesis focuses on diagnostics and vaccines against RVFV.

    RVFV infection kinetics was studied in a mouse model system by detection and quantification of viral genomes, using a developed quantitative real-time PCR (QRT-PCR) method. This novel QRT-PCR method proved to be reliable and serves as a supplement to standard diagnostics, direct virus isolation and serological methods. High levels of viral RNA were found in blood and liver samples from experimentally infected mice during the first days post infection. Thereafter the levels declined rapidly and dropped below detection limit approximately seven days post infection. The QRT-PCR technique was also used in a study aimed to improve diagnosis of RVFV from field samples collected on filter strips.

    Today, the available RVFV vaccines are only approved for animal use and these vaccines have several shortcomings. Since RVFV is a highly pathogenic organism requiring bio-safety level 3 laboratories, two different none-replicating vaccine approaches have been applied and evaluated using a mouse model. A DNA based vaccine, administered via gene-gun, and the use of virus-like particles (VLP), by the intra-peritoneal route. RVFV specific and neutralising antibodies were raised with both vaccine approaches. However, VLP vaccination against Rift valley Fever proved to be more promising as a future vaccine, since higher titres of neutralising antibodies and improved survival rate were found upon a lethal RVFV challenge in mice.

    In conclusion, a sensitive and specific method for quantifying RVFV infection and a promising vaccine candidate against RVFV were developed.

  • 258.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Drobni, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kerner, Alexander
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bucht, Göran
    Totalförsvarets forskningsinstitut, FOI, Umeå.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    PCR detection of a hantavirus and Rift Valley fever virus using dried whole blood spotted on filter stripsManuscript (preprint) (Other academic)
    Abstract [en]

    Viral hemorrhagic fevers are serious and emerging infections among humans and animals worldwide. Presently, blood or serum samples are the main source for diagnostics. However, transportation of such samples from remote areas may be complicated and expensive. Previously, filter strips soaked with blood have been used for detection of antibodies for diagnostics and epidemiological studies of several infectious diseases.

    In this study we evaluate if a similar approach could be applied for detection of viral RNA of Rift Valley Fever virus or Hantavirus (Puumala).

    We have used whole blood spiked with known amounts of viruses. In addition, clinical samples from patients with acute hemorrhagic fever with renal syndrome have been analysed. The samples were collected on filter strips and dried before RNA was extracted at different time-points. For Puumala, the sensitivity was acceptable, although the absolute levels of viral RNA were found to be considerable lower when using filter strips. The viral RNA could be detected and analysed after 2-3 weeks storage of the dried filter strips. In contrast, for RVFV, no or very low copy numbers of viral RNA were detected. Still, RVFV filter strips contained viable virus particles up to 48 h of storage.

    In conclusion, the use of dried whole blood samples spotted on filter strips for the detection of viral RNA seems to be a reliable and simple procedure for Hantaviruses. This procedure could be useful in field studies, especially in remote areas or low-income countries where transportation and storage of biological samples might be complicated. However, the result for RVFV was unexpected and further studies are needed to improve this technique.

  • 259.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Kerner, Alexander
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Drobni, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bucht, Göran
    Swedish Defence Research Agency, Department of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Detection of Puumala and Rift Valley Fever virus by quantitative RT-PCR and virus viability tests in samples of blood dried and stored on filter paper2011In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 178, no 1-2, p. 186-90Article in journal (Refereed)
    Abstract [en]

    Haemorrhagic fever viruses cause emerging infections worldwide, and blood or serum is the main sample used for diagnosis. However, storage and transportation of such samples from remote areas to regional laboratories may be complicated and expensive. In this study, a novel approach was evaluated for the detection of Puumala hantavirus (PUUV) RNA and Rift Valley fever virus (RVFV) RNA. Whole-blood samples spiked with viable virus particles were tested in parallel with clinical samples from patients with acute haemorrhagic fever with renal syndrome (nephropathia epidemica). Individual blood samples were spotted on filter paper, dried, and used for RNA extraction at later time points. PUUV RNA was detected by RT-PCR after storage at room temperature for up to six weeks. In contrast, only low copy numbers of RVFV RNA were detected after 1-2 days even though viable RVFV was eluted from the dried filter papers after the same time. The use of filter paper to collect and store blood samples for PUUV RNA detection is therefore a simple and reliable procedure. This approach might facilitate sampling and analysis of other RNA viruses from human or animal sources and could be used for field studies in remote areas or in developing countries.

  • 260.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lagerqvist, Nina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Habjan, Matthias
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Lundkvist, Ake
    Swedish Institute for Infectious Disease Control, SE-171 82 Solna, Sweden.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Weber, Friedemann
    Department of Virology, University of Freiburg, D-79008 Freiburg, Germany.
    Bucht, Göran
    Swedish Defence Research Agency, Department of CBRN Defence and Security, SE-901 82 Umeå, Sweden.
    Vaccination with virus-like particles protects mice from lethal infection of Rift Valley fever virus2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 385, no 2, p. 409-415Article in journal (Refereed)
    Abstract [en]

    Rift Valley Fever virus (RVFV) regularly accounts for severe and often lethal outbreaks among livestock and humans in Africa. Safe and effective veterinarian and human vaccines are highly needed. We present evidence that administration of RVF virus-like particles (VLPs) induces protective immunity in mice. In an accompanying paper, (Habjan, M., Penski, N., Wagner, V., Spiegel, M., Overby, A.K., Kochs, G., Huiskonen, J., Weber, F., 2009. Efficient production of Rift Valley fever virus-like particles: the antiviral protein MxA can inhibit primary transcription of Bunyaviruses. Virology 385, 400-408) we report the production of these VLPs in mammalian cells. After three subsequent immunizations with 1x10(6) VLPs/dose, high titers of virus-neutralizing antibodies were detected; 11 out of 12 mice were protected from challenge and only 1 out of 12 mice survived infection in the control groups. VLP vaccination efficiently suppressed replication of the challenge virus, whereas in the control animals high RNA levels and increasing antibody titers against the nucleocapsid protein indicated extensive viral replication. Our study demonstrates that the RVF VLPs are highly immunogenic and confer protection against RVFV infection in mice. In the test groups, the vaccinated mice did not exhibit any side effects, and the lack of anti-nucleocapsid protein antibodies serologically distinguished vaccinated animals from experimentally infected animals.

  • 261.
    Näslund, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Lagerqvist, Nina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lundkvist, Ake
    Evander, Magnus
    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
    Kinetics of Rift Valley fever virus in experimentally infected mice using quantitative real-time RT-PCR2008In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 151, no 2, p. 277-282Article in journal (Refereed)
    Abstract [en]

    Rift Valley Fever (RVF) is an important viral zoonosis in Africa affecting animals and humans. Since no protective vaccines or effective treatments are available for human use, accurate and reliable diagnostic methods are essential for surveillance of the disease in order to implement adequate public health actions. To study the kinetics of the RVF Virus (RVFV) infection, a SYBR Green-based quantitative real-time RT-PCR assay was developed. By using primers targeting the S-segment of RVFV, the detection limit of this assay was estimated to 30 RNA templates. Blood and organs of experimentally infected mice were sampled at different time points and RVFV RNA was quantified. High amounts of RVFV RNA were found in blood, brain, and liver samples shortly after infection with a 1-4 days post infection window for viral RNA detection. Mice developed symptoms after the appearance of serum antibodies, indicating that the host response plays an important role in the outcome of the disease. The RVFV quantitative RT-PCR proved to be a valuable diagnostic tool during the first days of infection, before detectable antibody levels and visual symptoms of RVF were observed.

  • 262. Obanda, Vincent
    et al.
    Michuki, George
    Jowers, Michael J.
    Rumberia, Cecilia
    Mutinda, Mathew
    Lwande, Olivia Wesula
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wangoru, Kihara
    Kasiiti-Orengo, Jacquiline
    Yongo, Moses
    Angelone-Alasaad, Samer
    COMPLETE GENOMIC SEQUENCE OF VIRULENT PIGEON PARAMYXOVIRUS IN LAUGHING DOVES (STREPTOPELIA SENEGALENSIS) IN KENYA2016In: Journal of Wildlife Diseases, ISSN 0090-3558, E-ISSN 1943-3700, Vol. 52, no 3, p. 599-608Article in journal (Refereed)
    Abstract [en]

    Following mass deaths of Laughing Doves (Streptopelia senegalensis) in different localities throughout Kenya, internal organs obtained during necropsy of two moribund birds were sampled and analyzed by next generation sequencing. We isolated the virulent strain of pigeon paramyxovirus type-1 (PPMV-1), PPMV1/Laughing Dove/Kenya/Isiolo/B2/2012, which had a characteristic fusion gene motif (110)GGRRQKRF(117). We obtained a partial full genome of 15,114 nucleotides. The phylogenetic relationship based on the fusion gene and genomic sequence grouped our isolate as class II genotype VI, a group of viruses commonly isolated from wild birds but potentially lethal to Chickens (Gallus gallus domesticus). The fusion gene isolate clustered with PPMV-I strains from pigeons (Columbidae) in Nigeria. The complete genome showed a basal and highly divergent lineage to American, European, and Asian strains, indicating a divergent evolutionary pathway. The isolated strain is highly virulent and apparently species-specific to Laughing Doves in Kenya. Risk of transmission of such a strain to poultry is potentially high whereas the cyclic epizootic in doves is a threat to conservation of wild Columbidae in Kenya.

  • 263.
    Olofsson, Anton
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Viral agents causing CNS infection in northern Sweden.2014Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 264.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Studie av larynxpapillom i norra Sverige: två fall av onkogena HPV bland 26 patienter2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 21, p. 1187-1189Article in journal (Refereed)
    Abstract [en]

    Laryngeal papilloma is associated with human papillomavirus (HPV) 6, 11, 16, 18 and 31. The variation in the frequency of surgical treatment between patients for the same subtypes of HPV is inconsistent and poorly understood. Comparisons of the female laryngeal papilloma group (n?=?8, median age 46 yrs) with the male (n= 18, median age 32 yrs) with respect to gender, age, time of disease, period of life for diagnosis, disease progression profile, frequency of surgery (CO2 laser) during time of disease, localisation of papilloma in the upper airway and HPV subtype did not reach significance. In contrast the comparison between the high frequency (Ž 1 treatment/yr, n?=?11, median age 31 yrs) and low frequency (<1 treatment/yr, n?=?15 median age 45 yrs) treatment groups with regard to the same parameters as the female-male comparison, showed a clear-cut higher median age in the low frequency group (P?=?0,01).

  • 265.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sjöstedt, M
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hellström, S
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The cytokine profile of T cells in the pharyngeal tonsil of childrenManuscript (preprint) (Other academic)
  • 266. Olofsson, Sigvard
    et al.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Dimock, Ken
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Avian influenza and sialic acid receptors: more than meets the eye?2005In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 5, no 3, p. 184-8Article in journal (Refereed)
    Abstract [en]

    Given our recent discoveries that the ocular human pathogens adenovirus serotype 37 and enterovirus serotype 70 use sialic acid linked to galactose via alpha2,3 glycosidic bonds as a cellular receptor, we propose that the presence of this receptor in the eye also explains the ocular tropism exhibited by zoonotic avian influenza A viruses such as subtype H5N1 in Hong Kong in 1997, H7N7 in the Netherlands in 2003, H7N2 in the USA in 2003, and H7N3 in Canada in 2004. We also draw attention to the implications this hypothesis may have for epizootic and zoonotic influenza, and the initiation of future pandemics.

  • 267.
    Olsson, Gert E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Verlemyr, Ann-Christin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    White, Neil
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Palo, R Thomas
    Hantavirus antibody occurrence in bank voles (Clethrionomys glareolus) during a vole population cycle2003In: Journal of Wildlife Diseases, ISSN 0090-3558, E-ISSN 1943-3700, Vol. 39, no 2, p. 299-305Article in journal (Refereed)
    Abstract [en]

    Puumala virus, genus Hantavirus, is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome. The bank vole (Clethrionomys glareolus) is the natural reservoir species of this hantavirus. We initiated sampling of bank voles at sites of recently identified human nephropathia epidemica cases and paired control sites in the fall of 1995 in coastal areas of northern Sweden. Sites were trapped annually in spring and fall until 1999. Prevalence of antibody to Puumala virus was similar among local bank vole populations in the two types of sites over time. During peak years, however, the absolute number of bank voles was higher in case sites than control sites. Consequently, the likelihood of Puumala virus exposure was increased at case sites during population highs. This would imply that the risk of Puumala virus exposure to conspecifics and humans is habitat and site dependent with a temporal component.

  • 268.
    Olsson, Gert E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Dalerum, Fredrik
    Hörnfeldt, Birger
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Palo, Thomas R
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Human hantavirus infections, Sweden.2003In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 9, no 11, p. 1395-401Article in journal (Refereed)
    Abstract [en]

    The prevalent human hantavirus disease in Sweden is nephropathia epidemica, which is caused by Puumala virus and shed by infected bank voles (Clethrionomys glareolus). To evaluate temporal and spatial patterns of this disease, we studied 2,468 reported cases from a highly disease-endemic region in northern Sweden. We found that, in particular, middle-aged men living in rural dwellings near coastal areas were overrepresented. The case-patients were most often infected in late autumn, when engaged in activities near or within manmade rodent refuges. Of 862 case-patients confident about the site of virus exposure, 50% were concentrated within 5% of the study area. The incidence of nephropathia epidemica was significantly correlated with bank vole numbers within monitored rodent populations in part of the region. Understanding this relationship may help forestall future human hantavirus outbreaks.

  • 269.
    Olsson, Gert E
    et al.
    Institutionen för vilt, fisk och miljö, Sveriges lantbruksuniversitet, Umeå.
    Hjertqvist, Marika
    Epidemiologiska avdelningen, Smittskyddsinstitutet, Solna.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hörnfeldt, Birger
    Institutionen för vilt, fisk och miljö, Sveriges lantbruksuniversitet, Umeå.
    Sorkfeberprognos: sorkdata pekar på nytt, stort utbrott2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 29-31, p. 1769-1770Article in journal (Other academic)
  • 270.
    Olsson, Gert E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    White, Neil
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Verlemyr, Ann-Christin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Palo, R Thomas
    Demographic factors associated with hantavirus infection in bank voles (Clethrionomys glareolus)2002In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 8, no 9, p. 924-929Article in journal (Refereed)
    Abstract [en]

    The bank vole (Clethrionomys glareolus) is the natural reservoir of Puumala virus (PUUV), a species in the genus Hantavirus. PUUV is the etiologic agent of nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome. Factors that influence hantavirus transmission within host populations are not well understood. We evaluated a number of factors influencing on the association of increased PUUV infection in bank voles captured in a region in northern Sweden endemic for the virus. Logistic regression showed four factors that together correctly predicted 80% of the model outcome: age, body mass index, population phase during sampling (increase, peak, or decline/low), and gender. This analysis highlights the importance of population demography in the successful circulation of hantavirus. The chance of infection was greatest during the peak of the population cycle, implying that the likelihood of exposure to hantavirus increases with increasing population density.

  • 271.
    Olsson, Gert E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    White, Neil
    Department of Primary Industries and Fisheries, Toowoomba, Australia.
    Hjältén, Joakim
    Department of Animal Ecology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Habitat factors associated with bank voles (Clethrionomys glareolus) and concomitant hantavirus in northern Sweden2005In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 5, no 4, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Puumala virus (PUUV), genus hantavirus, causes nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome in humans. In this study, bank voles, the natural reservoir of PUUV, were captured at locations of previous human PUUV exposure and paired controls within a region of high incidence in northern Sweden. The aim of the study was to evaluate the influence of environmental factors on the abundance of bank voles and the occurrence of PUUV. The total number of voles and the number of PUUV-infected voles did not differ between locations of previous human PUUV exposure and paired controls. The number of bank voles expressing antibodies to PUUV infection increased linearly with total bank vole abundance implying density independent transmission. Using principal component and partial correlation analysis, we found that particular environmental characteristics associated with old-growth moist forests (i.e., those dominated by Alectoria spp., Picea abies, fallen wood, and Vaccinium myrtillus) were also associated with increased abundance of bank vole and hence the number of PUUV-infected bank voles, whereas there were no correlations with factors associated with dry environments (i.e., Pinus sylvestris and V. vitis-idea). This suggests that circulation and persistence of PUUV within bank vole populations was influenced by habitat factors. Future modeling of risk of exposure to hantavirus and transmission of PUUV within vole populations should include the influence of these factors.

  • 272.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh Drott, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Laurantzon, Lovisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Laurantzon, Oscar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Chronic prostatic infection and inflammation by propionibacterium acnes in a rat prostate infection model2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51434-Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic inflammation may be induced by P. acnes infection.

  • 273.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Davidsson, Sabina
    Örebro Univ Hosp, Dept Urol, Örebro, Sweden.
    Unemo, Magnus
    Örebro Univ Hosp, Dept Lab Med, Örebro, Sweden.
    Mölling, Paula
    Örebro Univ Hosp, Dept Lab Med, Örebro, Sweden.
    Andersson, Swen-Olov
    Örebro Univ Hosp, Dept Urol, Örebro, Sweden.
    Andrén, Ove
    Örebro Univ Hosp, Dept Urol, Örebro, Sweden.
    Söderquist, Bo
    Örebro Univ Hosp, Dept Lab Med, Örebro, Sweden.
    Sellin, Mats
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Antibiotic susceptibility in prostate-derived Propionibacterium acnes isolates2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 10, p. 778-785Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine antibiotic susceptibility of Propionibacterium acnes isolates from prostate. Prostate-derived P. acnes isolates (n = 24, Umeå & Örebro, Sweden, 2007-2010) and a panel of control strains (n = 25, Sweden) collected from skin and deep infections were assessed for resistance to penicillin G, piperacillin-tazobactam, imipenem, gentamicin, azithromycin, erythromycin, vancomycin, ciprofloxacin, moxifloxacin, tetracycline, tigecycline, fusidic acid, clindamycin, rifampicin, linezolid, daptomycin, trimethoprim-sulfamethoxazole, and metronidazole. In addition, the isolates were tested for inducible clindamycin resistance. All prostate derived P. acnes isolates displayed wild-type distribution of MIC-values, without evidence of acquired resistance. In the reference panel, 5 of 25 isolates had acquired macrolide resistance with cross-resistance to azithromycin, clindamycin, and erythromycin. In addition, one of these isolates was resistant to tetracycline.

  • 274.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Laboratory Medicine, Clinical Microbiology, Umeå University Hospital, Umeå, Sweden.
    Honkala, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomqvist, Bert
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Laboratory Medicine, Clinical Microbiology, Umeå University Hospital, Umeå, Sweden.
    Kok, Eloise
    Weidung, Bodil
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Urea dilution of serum for reproducible anti-HSV1 IgG avidity index2019In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 19, article id 164Article in journal (Refereed)
    Abstract [en]

    Herpes simplex virus type 1 (HSV1), establishes life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe a protocol to generate a reliable and discriminative avidity index (AI) for anti-HSV1 IgG content in human sera. Human serum from two distinct cohorts; one a biobank collection (Betula) (n = 28), and one from a clinical diagnostics laboratory at Northern Sweden University Hospital (NUS) (n = 18), were assessed for presence of IgG antibodies against HSV1 by a commercially available ELISA-kit. Addition of urea at the incubation step reduces effective binding, and the ratio between urea treated sample and non-treated sample was used to express an avidity index (AI) for individual samples. AI score ranged between 43.2 and 73.4% among anti-HSV1 positive biobank sera. Clinical samples ranged between 36.3 and 74.9%. Reproducibility expressed as an intraclass correlation coefficient (ICC) was estimated at 0.948 (95% CI: 0.900-0.979) and 0.989 (95% CI 0.969-0.996) in the biobank and clinical samples, respectively. The method allows for AI scoring of anti-HSV1 IgG from individual human sera with a single measurement. The least significant change between two measurements at the p < 0.05 level was estimated at 5.4 and 3.2 points, respectively, for the two assessed cohorts.

  • 275.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kok, Eloise
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Herpes virus seroepidemiology in the adult Swedish population2017In: Immunity & Ageing, ISSN 1742-4933, E-ISSN 1742-4933, Vol. 14, article id 10Article in journal (Refereed)
    Abstract [en]

    Background: Herpes viruses establish a life-long latency and can cause symptoms during both first-time infection and later reactivation. The aim of the present study was to describe the seroepidemiology of Herpes simplex type 1 (HSV1), Herpes simplex type 2 (HSV2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV) and Human herpes virus type 6 (HHV6) in an adult Swedish population (35-95 years of age). Methods: Presence of antibodies against the respective viruses in serum from individuals in the Betula study was determined with an enzyme-linked immunosorbent assay (ELISA). Singular samples from 535 persons (53.9% women, mean age at inclusion 62.7 +/- 14.4 years) collected 2003-2005 were analyzed for the five HHVs mentioned above. In addition, samples including follow-up samples collected 1988-2010 from 3,444 persons were analyzed for HSV. Results: Prevalence of HSV1 was 79.4%, HSV2 12.9%, CMV 83.2%, VZV 97.9%, and HHV6 97.5%. Herpes virus infections were more common among women (p = 0.010) and a lower age-adjusted HSV seroprevalence was found in later birth cohorts (p < 0.001). The yearly incidence of HSV infection was estimated at 14.0/1000. Conclusion: Women are more often seropositive for HHV, especially HSV2. Age-adjusted seroprevalence for HSV was lower in later birth cohorts indicating a decreasing childhood and adolescent risk of infection.

  • 276.
    Olsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Honkala, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Karhunen, Pekka J.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kok, Eloise H.
    HSV presence in brains of individuals without dementia: the TASTY brain series2016In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 11, p. 1349-1355Article in journal (Refereed)
    Abstract [en]

    Herpes simplex virus (HSV) type 1 affects a majority of the population and recent evidence suggests involvement in Alzheimer's disease aetiology. We investigated the prevalence of HSV type 1 and 2 in the Tampere Autopsy Study (TASTY) brain samples using PCR and sero-positivity in plasma, and associations with Alzheimer's disease neuropathology. HSV was shown to be present in human brain tissue in 11/584 (1.9%) of samples in the TASTY cohort, of which six had Alzheimer's disease neuropathological amyloid beta (A beta) aggregations. Additionally, serological data revealed 86% of serum samples tested were IgG-positive for HSV. In conclusion, we report epidemiological evidence of the presence of HSV in brain tissue free from encephalitis symptoms in a cohort most closely representing the general population (a minimum prevalence of 1.9%). Whereas 6/11 samples with HSV DNA in the brain tissue had A beta aggregations, most of those with A beta aggregations did not have HSV present in the brain tissue.

  • 277.
    Panayiotou, Christakis
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Pasto, Jenny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Upadhyay, Arunkumar S.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation2018In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e02054-17Article in journal (Refereed)
    Abstract [en]

    Flaviviruses are arthropod-borne viruses that constitute a major global health problem, with millions of human infections annually. Their pathogenesis ranges from mild illness to severe manifestations such as hemorrhagic fever and fatal encephalitis. Type I interferons (IFNs) are induced in response to viral infection and stimulate the expression of interferon-stimulated genes (ISGs), including that encoding viperin (virus-inhibitory protein, endoplasmic reticulum associated, IFN inducible), which shows antiviral activity against a broad spectrum of viruses, including several flaviviruses. Here we describe a novel antiviral mechanism employed by viperin against two prominent flaviviruses, tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin was found to interact and colocalize with the structural proteins premembrane (prM) and envelope (E) of TBEV, as well as with nonstructural (NS) proteins NS2A, NS2B, and NS3. Interestingly, viperin expression reduced the NS3 protein level, and the stability of the other interacting viral proteins, but only in the presence of NS3. We also found that although viperin interacted with NS3 of mosquito-borne flaviviruses (ZIKV, Japanese encephalitis virus, and yellow fever virus), only ZIKV was sensitive to the antiviral effect of viperin. This sensitivity correlated with viperin's ability to induce proteasome-dependent degradation of NS3. ZIKV and TBEV replication was rescued completely when NS3 was overexpressed, suggesting that the viral NS3 is the specific target of viperin. In summary, we present here a novel antiviral mechanism of viperin that is selective for specific viruses in the genus Flavivirus, affording the possible availability of new drug targets that can be used for therapeutic intervention.

    IMPORTANCE Flaviviruses are a group of enveloped RNA viruses that cause severe diseases in humans and animals worldwide, but no antiviral treatment is yet available. Viperin, a host protein produced in response to infection, effectively restricts the replication of several flaviviruses, but the exact molecular mechanisms have not been elucidated. Here we have identified a novel mechanism employed by viperin to inhibit the replication of two flaviviruses: tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin induced selective degradation via the proteasome of TBEV and ZIKV non-structural 3 (NS3) protein, which is involved in several steps of the viral life cycle. Furthermore, viperin also reduced the stability of several other viral proteins in a NS3-dependent manner, suggesting a central role of NS3 in viperin's antiflavivirus activity. Taking the results together, our work shows important similarities and differences among the members of the genus Flavivirus and could lead to the possibility of therapeutic intervention.

  • 278.
    Persson, B David
    et al.
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Müller, Steffen
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Reiter, Dirk M
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Schmitt, Benedikt B T
    Institute for Physical and Theoretical Chemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Marttila, Marko
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sumowski, Chris Vanessa
    Institute for Physical and Theoretical Chemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Schweizer, Sabine
    Institute for Physical and Theoretical Chemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Scheu, Ulrike
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Ochsenfeld, Christian
    Institute for Physical and Theoretical Chemistry, University of Tübingen, D-72076 Tübingen, Germany.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Stehle, Thilo
    Interfaculty Institute for Biochemistry, University of Tübingen, D-72076 Tübingen, Germany.
    An arginine switch in the species B adenovirus knob determines high-affinity engagement of cellular receptor CD46.2009In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, no 2, p. 673-686Article in journal (Refereed)
    Abstract [en]

    Adenoviruses (Ads) are icosahedral, nonenveloped viruses with a double-stranded DNA genome. The 51 known Ad serotypes exhibit profound variations in cell tropism and disease types. The number of observed Ad infections is steadily increasing, sometimes leading to fatal outcomes even in healthy individuals. Species B Ads can cause kidney infections, hemorrhagic cystitis, and severe respiratory infections, and most of them use the membrane cofactor protein CD46 as a cellular receptor. The crystal structure of the human Ad type 11 (Ad11) knob complexed with CD46 is known; however, the determinants of CD46 binding in related species B Ads remain unclear. We report here a structural and functional analysis of the Ad11 knob, as well as the Ad7 and Ad14 knobs, which are closely related in sequence to the Ad11 knob but have altered CD46-binding properties. The comparison of the structures of the three knobs, which we determined at very high resolution, provides a platform for understanding these differences and allows us to propose a mechanism for productive high-affinity engagement of CD46. At the center of this mechanism is an Ad knob arginine that needs to switch its orientation in order to engage CD46 with high affinity. Quantum chemical calculations showed that the CD46-binding affinity of Ad11 is significantly higher than that of Ad7. Thus, while Ad7 and Ad14 also bind CD46, the affinity and kinetics of these interactions suggest that these Ads are unlikely to use CD46 productively. The proposed mechanism is likely to determine the receptor usage of all CD46-binding Ads.

  • 279. Persson, B David
    et al.
    Reiter, Dirk M
    Marttila, Marko
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Casasnovas, José M
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Stehle, Thilo
    Adenovirus type 11 binding alters the conformation of its receptor CD46.2007In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 14, no 2, p. 164-166Article in journal (Refereed)
    Abstract [en]

    Adenoviruses (Ads) are important human pathogens and valuable gene delivery vehicles. We report here the crystal structure of the species B Ad11 knob complexed with the Ad11-binding region of its receptor CD46. The conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. This mechanism of interaction is likely to be conserved among many pathogens that target CD46 or related molecules.

  • 280.
    Pettersson, Amanda
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Development of Serological Methods for Rhinovirus Diagnosis2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 281.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Boman, Jens
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Outbreak of Puumala virus infection, Sweden.2008In: Emerging infectious diseases, ISSN 1080-6059, Vol. 14, no 5, p. 808-10Article in journal (Refereed)
    Abstract [en]

    An unexpected and large outbreak of Puumala virus infection in Sweden resulted in 313 nephropathia epidemica patients/100,000 persons in Västerbotten County during 2007. An increase in the rodent population, milder weather, and less snow cover probably contributed to the outbreak.

  • 282.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Klingström, Jonas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hardestam, Jonas
    Lundkvist, Ake
    Smittskyddsinstitutet.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hantavirus RNA in saliva from patients with hemorrhagic fever with renal syndrome.2008In: Emerging infectious diseases, ISSN 1080-6059, Vol. 14, no 3, p. 406-11Article in journal (Refereed)
    Abstract [en]

    Hantaviruses cause 2 zoonotic diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome. Infection is usually initiated after inhalation of virus-contaminated rodent excreta. In addition to the zoonotic infection route, growing evidence suggests person-to-person transmission of Andes virus. For this reason, we studied whether saliva from HFRS patients contained hantavirus. During an outbreak in northern Sweden of nephropathia epidemica (NE), a milder form of hemorrhagic fever with renal syndrome, we collected saliva and plasma from 14 hospitalized NE patients with verified Puumala virus (PUUV) infection. PUUV RNA was detected in saliva from 10 patients (range 1,530-121,323 PUUV RNA copies/mL) by quantitative reverse transcription-PCR. The PUUV S-segment sequences from saliva and plasma of the same patients were identical. Our data show that hantavirus RNA could be detected in human saliva several days after onset of disease symptoms and raise the question whether interhuman transmission of hantavirus may occur through saliva.

  • 283.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Rasmuson, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hantavirus-specific IgA in saliva and viral antigen in the parotid gland in patients with hemorrhagic fever with renal syndrome2011In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 5, p. 864-870Article in journal (Refereed)
    Abstract [en]

    The Hantavirus genus comprises rodent borne, zoonotic viruses of the Bunyaviridae family that cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Rodent saliva contains infectious hantavirus and evidence suggests that hantavirus is also shed in human saliva, but person-to-person transmission is rare. In saliva, immunoglobulin (Ig) A is the predominant immunoglobulin class. Secretory IgA serves as an important first line of defence on epithelial surfaces and the binding of secretory IgA to pathogens can inhibit adherence of microorganisms to mucosal cells and neutralize viruses. This study investigated the presence and importance of salivary IgA in relation to viral antigen in the saliva by testing Puumala hantavirus (PUUV) specific IgA, and RNA in saliva in acutely ill patients with HFRS. In saliva samples, PUUV specific IgA was detected in 12 of 33 (36%) patients with HFRS and 20 (61%) were PUUV RNA positive. There was a statistically significant inverse association between the presence of salivary IgA antibodies and PUUV RNA in the saliva. PUUV-specific IgA in saliva was not found in a long-term follow-up, while PUUV IgA in serum was detected in three patients, 28-32 months after the initial study. Notably, both PUUV RNA and PUUV nucleocapsid antigen were detected in endothelial cells within the parotid gland of a deceased patient with HFRS. J. Med. Virol. 83:864-870, 2011. © 2011 Wiley-Liss, Inc.

  • 284.
    Pettersson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Klingström, Jonas
    Department of medicine, Center for Infectious Medicine, Karolinska institutet, Stockholm.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment2014In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 3, p. 235-241Article in journal (Refereed)
    Abstract [en]

    Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients.

  • 285. Peña Cárcamo, José R.
    et al.
    Morell, María L.
    Vázquez, Cecilia A.
    Vatansever, Sezen
    Upadhyay, Arunkumar S.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cordo, Sandra M.
    García, Cybele C.
    The interplay between viperin antiviral activity, lipid droplets and Junín mammarenavirus multiplication2018In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 514, p. 216-229Article in journal (Refereed)
    Abstract [en]

    Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease.

  • 286. Pukkala, Eero
    et al.
    Andersen, Aage
    Berglund, Göran
    Gislefoss, Randi
    Gudnason, Vilmundur
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jellum, Egil
    Jousilahti, Pekka
    Knekt, Paul
    Koskela, Pentti
    Kyyrönen, P Pentti
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Luostarinen, Tapio
    Löve, Arthur
    Ögmundsdóttir, Helga
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Tenkanen, Leena
    Tryggvadóttir, Laufey
    Virtamo, Jarmo
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Virologi.
    Widell, Anders
    Lehtinen, Matti
    Dillner, Joakim
    Nordic biological specimen banks as basis for studies of cancer causes and control - more than 2 million sample donors, 25 million person years and 100 000 prospective cancers.2007In: Acta Oncol, ISSN 0284-186X, Vol. 46, no 3, p. 286-307Article in journal (Refereed)
  • 287.
    Rajan, Anandi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Capsid protein functions of enteric human adenoviruses2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human adenoviruses (HAdVs) cause respiratory illnesses, epidemic conjunctivitis and infantile gastroenteritis. HAdV types 40 and 41 cause enteric infections in infants worldwide. HAdVs use various receptors for attachment onto different host cells. Coxsackievirus and adenovirus receptor, CD46, sialic acid, coagulation factors IX and X, lactoferrin and heparan sulfate are some receptors and molecules which the hexon and fiber proteins (components of the capsid) bind for direct or indirect cellular attachment. The penton base protein (another component of the capsid) is responsible for the internalization of the virus into the host cell. An arginine-glycine-aspartic acid amino acid motif is present in most but not all adenovirus penton base proteins and mediates interaction with αv integrins, resulting in internalization.

    The enteric HAdVs are unique since they do not have this arginine-glycine-aspartic acid motif on their penton base. Using a library of hamster cells expressing specific human integrins, along with recombinant soluble penton base from HAdV type 41 and commercially available soluble laminins, we identified laminin-binding integrins as co-receptors for entry and infection of human intestinal HT-29 cells by the enteric HAdVs.

    HAdV types 40, 41 and 52 are the only three HAdVs that have two different fiber proteins, one long and one short. By performing cell binding and infection experiments, we have found that the receptor for the short fiber of HAdV-52 is sialic acid-containing glycans and the long fiber receptor is CAR although most of the binding was dependent on sialic acid-containing glycans. We also observed that the short fiber of HAdV type 40 interacts with soluble heparin or cell surface heparan sulfate. Further investigation pointed out that the specific sulfate groups on heparin/heparan sulfate (sulfated glycosaminoglycans) are important for this binding. Also, we identified that the interaction and utilization of these glycosaminoglycans as receptors is dependent on exposure to low pH. We also studied the potential mechanism behind the symptoms caused by these enteric HAdVs in enteroendocrine cells called enterochromaffin cells. We could show that the short fiber and the hexon of HAdV type 41 stimulated release of serotonin from the enterochromaffin cells, which can be a cause of vomiting and diarrhea.

    These studies have given us insight into the role of enteric HAdV capsid proteins as ligands to hitherto unidentified receptors and co-receptors. We also show that these molecules play important functions in the virus’ infectious cycle and probably also in their disease mechanism of host cells.

  • 288.
    Rajan, Anandi
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Trulsson, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Palm, Elin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mundigl, Sarah
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Low pH primes short fibers of enteric human adenoviruses to use heparan sulfate as a cellular receptorManuscript (preprint) (Other academic)
  • 289.
    Rajan, Anandi
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Persson, B. David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. 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, Molecular Infection Medicine Sweden (MIMS).
    Olofsson, Annelie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Heino, Jyrki
    Department of Biochemistry, University of Turku, Finland.
    Takada, Yoshikazu
    Department of Dermatology, Biochemistry and Molecular Medicine, UC Davis School of Medicine, California, USA.
    Mould, A. Paul
    Biomolecular Analysis Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.
    Schnapp, Lynn M.
    Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, USA.
    Gall, Jason
    Vaccine Research Center (VRC), NIAID, NIH, Bethesda, USA.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of Ht-29 cells2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 10019Article in journal (Refereed)
    Abstract [en]

    The enteric species F human adenovirus types 40 and 41 (HAdV-40 and -41) are the third most common cause of infantile gastroenteritis in the world. Knowledge about HAdV-40 and -41 cellular infection is assumed to be fundamentally different from that of other HAdVs since HAdV-40 and -41 penton bases lack the αV-integrin-interacting RGD motif. This motif is used by other HAdVs mainly for internalization and endosomal escape. We hypothesised that the penton bases of HAdV-40 and -41 interact with integrins independently of the RGD motif. HAdV-41 transduction of a library of rodent cells expressing specific human integrin subunits pointed to the use of laminin-binding α2-, α3- and α6-containing integrins as well as other integrins as candidate co-receptors. Specific laminins prevented internalisation and infection, and recombinant, soluble HAdV-41 penton base proteins prevented infection of human intestinal HT-29 cells. Surface plasmon resonance analysis demonstrated that HAdV-40 and -41 penton base proteins bind to α6-containing integrins with an affinity similar to that of previously characterised penton base:integrin interactions. With these results, we propose that laminin-binding integrins are co-receptors for HAdV-40 and -41.

  • 290.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrman, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Haney, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus2011In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, no 5, p. 685-690Article in journal (Refereed)
    Abstract [en]

    Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide.

  • 291.
    Rasmuson, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mohamed, Nahla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Cytotoxic immune responses in the lungs correlate to disease severity in patients with hantavirus infection2016In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 35, no 4, p. 713-721Article in journal (Refereed)
    Abstract [en]

    Hantavirus infections may cause severe and sometime life-threatening lung failure. The pathogenesis is not fully known and there is an urgent need for effective treatment. We aimed to investigate the association between pulmonary viral load and immune responses, and their relation to disease severity. Bronchoscopy with sampling of bronchoalveolar lavage (BAL) fluid was performed in 17 patients with acute Puumala hantavirus infection and 16 healthy volunteers acting as controls. Lymphocyte subsets, granzyme concentrations, and viral load were determined by flow cytometry, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (RT-PCR), respectively. Analyses of BAL fluid revealed significantly higher numbers of activated CD8+ T cells and natural killer (NK) cells, as well as higher concentrations of the cytotoxins granzymes A and B in hantavirus-infected patients, compared to controls. In patients, Puumala hantavirus RNA was detected in 88 % of BAL cell samples and correlated inversely to the T cell response. The magnitude of the pulmonary cytotoxic lymphocyte response correlated to the severity of disease and systemic organ dysfunction, in terms of need for supplemental oxygen treatment, hypotension, and laboratory data indicating renal failure, cardiac dysfunction, vascular leakage, and cell damage. Regulatory T cell numbers were significantly lower in patients compared to controls, and may reflect inadequate immune regulation during hantavirus infection. Hantavirus infection elicits a pronounced cytotoxic lymphocyte response in the lungs. The magnitude of the immune response was associated with disease severity. These results give insights into the pathogenesis and possibilities for new treatments.

  • 292. Rebetz, Johan
    et al.
    Na, Manli
    Su, Changqing
    Holmqvist, Bo
    Edqvist, Anna
    Nyberg, Cecilia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Widegren, Bengt
    Salford, Leif G
    Sjögren, Hans Olov
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Qian, Qijun
    Fan, Xiaolong
    Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence2009In: PloS one, ISSN 1932-6203, Vol. 4, no 12, p. e8484-Article in journal (Refereed)
    Abstract [en]

    The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.

  • 293. Rezelj, Veronica V
    et al.
    Överby, Anna K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elliott, Richard M
    Generation of mutant Uukuniemi viruses lacking the nonstructural protein NSs by reverse genetics indicates that NSs is a weak interferon antagonist.2015In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 89, no 9, p. 4849-4856Article in journal (Refereed)
    Abstract [en]

    Uukuniemi virus (UUKV) is a tick-borne member of the Phlebovirus genus (family Bunyaviridae) and has been widely used as a safe laboratory model to study aspects of bunyavirus replication. Recently, a number of new tick-borne phleboviruses have been discovered, some of which, like severe fever with thrombocytopenia syndrome virus and Heartland virus, are highly pathogenic in man. UUKV could now serve as a useful comparator to understand the molecular basis for the different pathogenicities of these related viruses. We established a reverse genetics system to recover UUKV entirely from cDNA clones. We generated two recombinant viruses, one in which the nonstructural protein NSs open reading frame was deleted from the S segment and one in which the NSs gene was replaced with GFP, allowing convenient visualization of viral infection. We show that the UUKV NSs protein acts as a weak interferon antagonist in human cells, but it is unable to completely counteract the interferon response, which could serve as an explanation for its inability to cause disease in man.

    IMPORTANCE: Uukuniemi virus (UUKV) is a tick-borne phlebovirus that is apathogenic for man and has been used as a convenient model to investigate aspects of phlebovirus replication. Recently new tick-borne phleboviruses have emerged, such as severe fever with thrombocytopenia syndrome virus in China and Heartland virus in the US, that are highly pathogenic, and UUKV will now serve as a comparison to aid understanding of the molecular basis for the virulence of these new viruses. To help such investigations, we have developed a reverse genetics system for UUKV that permits manipulation of the viral genome. We generated viruses lacking the nonstructural protein NSs and show that UUKV NSs is a weak interferon antagonist. In addition, we created a virus that expresses GFP and thus allows convenient monitoring of virus replication. These new tools represent a significant advance in the study of tick-borne phleboviruses.

  • 294. Roffey, R
    et al.
    Lantorp, K
    Tegnell, A
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Biological weapons and bioterrorism preparedness: importance of public-health awareness and international cooperation2002In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 8, no 8, p. 522-528Article in journal (Refereed)
    Abstract [en]

    Biological weapons and biological terrorism have recently come into focus due to the deliberate release of Bacillus anthracis via mail delivered in the USA. Since the 1930s, biological weapons have been developed in a number of countries. In 1975, the Biological and Toxin Weapons Convention entered into force; this prohibits the use of these weapons and has been signed by a large majority of countries (144). Unfortunately, several countries failed to respect this treaty. The Soviet Union continued and expanded its biological weapons program, and after the Gulf War it was revealed that Iraq also had an extensive biological weapons program. Large-scale deliberate release of, Bacillus anthracis, for example, or an epidemic following a release of smallpox virus, would have a devastating effect. This has motivated the world community to strengthen the Biological and Toxin Weapons Convention with a control mechanism which has, as yet, not been successful. Sweden, like other countries, is enhancing its preparedness with regard to stocks of antibiotics and vaccines, related to these improving the diagnostics these and similar agents, and is setting up an epidemiologic task force that can be used in infectious disease emergencies such as the deliberate release of biological warfare agents. International cooperation in this area has to be enhanced, not least in the European Union.

  • 295. Roffey, R
    et al.
    Tegnell, A
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Biological warfare in a historical perspective2002In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 8, no 8, p. 450-454Article in journal (Refereed)
    Abstract [en]

    There are some early examples of biological warfare (BW), but in modern times it was used first for sabotage by Germany during WWI. Development of biological weapons on a military significant scale was initiated in several countries in the period between the world wars. During WWII, several countries had active programs such as the USA, UK, Canada, Germany, Japan and the Soviet Union. It was only Japan that on a fairly large scale used BW. The US program continued until 1969, when President Nixon took a decision to end it in connection with signing the BTWC. The Soviet Union had also continued its program after the war, and this was enhanced after signing the BTWC: in the 1980s the program consisted of around fifty facilities and involved around 60,000 people. The Soviet Union produced and maintained a large stockpile of BW-agents. After the collapse of the Soviet Union, and due to pressure from USA and UK, President Yeltsin issued a decree in 1992 banning continued offensive BW activity. However, there are still concerns of residual activity in Russia. Another program of concern is the Iraqi BW-program. After 10 years of UN inspections that were stopped in 1998, there are still many unanswered questions concerning the BW program. There was also a covert BW-program in South Africa that was terminated around 1993. There have also been a number of allegations of alleged use or possession. In addition, there are indications that 10-12 states are now trying to acquire BW, and this assessment is based on intelligence information, mainly from the USA. For example Iraq, North Korea, Iran, Syria, Sudan and Libya. Another aspect is the strong driving force of technology developments to promote this type of program, opening new risks for future potential military misuse.

  • 296. Roffey, Roger
    et al.
    Lantorp, Kurt
    Tegnell, Anders
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    [Update on biological weapons and bioterrorism. Important that health services pay attention to unusual events]2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, no 50, p. 5746-5752Article in journal (Other academic)
    Abstract [en]

    Biological weapons and biological terrorism have recently been in focus due to the deliberate release of Bacillus anthracis via mail delivered in the USA. Since the 1930s biological weapons have been developed in a number of countries. In 1975 a biological and toxin weapons convention prohibiting the use of these weapons were signed by a large majority of world countries. Unfortunately, a number of countries have failed to respect this treaty. The Soviet union continued and expanded its biological weapons program and after the Gulf war it was revealed that Iraq also had an extensive bio-weapons program. Large scale deliberate release of for example B. anthracis or an epidemic following a release of smallpox virus would have a devastating effect. This has urged the world community to strengthen the biological and toxin weapons convention with a control function which as of yet has not been successful. Furthermore, many countries including Sweden, increase stocks of antibiotics and smallpox vaccines. Sweden is also increasing preparedness regarding diagnostics of these and similar agents and is setting up an epidemiological task force that can be used in infectious disease emergencies such as the deliberate release of a biological weapon.

  • 297. Rusiol, Marta
    et al.
    Fernandez-Cassi, Xavier
    Hundesa, Ayalkibet
    Vieira, Carmen
    Kern, Anita
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ziros, Panos
    Kay, David
    Miagostovich, Marize
    Vargha, Marta
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Vantarakis, Apostolos
    Wyn-Jones, Peter
    Bofill-Mas, Silvia
    Girones, Rosina
    Application of human and animal viral microbial source tracking tools in fresh and marine waters from five different geographical areas2014In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 59, p. 119-129Article in journal (Refereed)
    Abstract [en]

    Integrated river basin management planning to mitigate the impacts of economic, demographic and climate change is an important issue for the future protection of water resources. Identifying sources of microbial contamination via the emerging science of Microbial Source Tracking (MST) plays a key role in risk assessment and the design of remediation strategies. Following an 18-month surveillance program within the EU-FP7-funded VIROCLIME project, specific MST tools were used to assess human markers such as adenoviruses (HAdV) and JC polyomaviruses (JCPyV) and porcine and bovine markers such as porcine adenoviruses (PAdV) and bovine polyomaviruses (BPyV) via quantification with real-time PCR to analyze surface water collected from five sites within different climatic zones: the Negro River (Brazil), Glafkos River (Greece), Tisza River (Hungary), Llobregat River (Spain) and Umealven River (Sweden). The utility of the viral MST tools and the prevalence and abundance of specific human and animal viruses in the five river catchments and adjacent seawater, which is impacted by riverine contributions from the upstream catchments, were examined. In areas where no sanitation systems have been implemented, sewage can directly enter surface waters, and river water exhibited high viral loads; HAdV and JCPyV could be detected at mean concentrations of 10(5) and 10(4) Genome Copies/Liter (GC/L), respectively. In general, river water samples upstream of urban discharges presented lower human viral loads than downstream sampling sites, and those differences appeared to increase with urban populations but decrease in response to high river flow, as the elevated river water volume dilutes microbial loads. During dry seasons, river water flow decreases dramatically, and secondary effluents can represent the bulk of the riverine discharge. We also observed that ice cover that formed over the river during the winter in the studied areas in North Europe could preserve viral stability due to the low temperatures and/or the lack of solar inactivation. Porcine and bovine markers were detected where intensive livestock and agricultural activities were present; mean concentration values of 10(3) GC/L indicated that farms were sometimes unexpected and important sources of fecal contamination in water. During spring and summer, when livestock is outdoors and river flows are low, animal pollution increases due to diffuse contamination and direct voiding of feces onto the catchment surface. The field studies described here demonstrate the dynamics of fecal contamination in all catchments studied, and the data obtained is currently being used to develop dissemination models of fecal contamination in water with respect to future climate change scenarios. The results concerning human and animal targets presented in this study demonstrate the specificity and applicability Of the viral quantitative parameters developed to widely divergent geographical areas and their high interest as new indicators of human and animal fecal contamination in water and as MST tools.

  • 298. Sahdo, Berolla
    et al.
    Särndahl, Eva
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Söderquist, Bo
    Propionibacterium acnes activates caspase-1 in human neutrophils2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 7, p. 652-663Article in journal (Refereed)
    Abstract [en]

    Propionibacterium acnes is a Gram-positive, slow-growing, anaerobic bacillus, predominantly found as a commensal on the skin and mucous membranes of adults. It is, however, also considered an opportunistic pathogen; mostly associated with acne vulgaris, but rarely also with severe infections such as infective endocarditis, prosthetic joint infections, and deep sternal wound infections following cardiothoracic surgery. In addition, P. acnes has recently been found in high frequency in prostate tissue from patients with prostatitis and prostate cancer. The NOD-like receptors (NLR) act as intracellular sensors of microbial components, and a number of various bacteria have been found to induce assembling and activation of NLR-inflammasomes; leading to a pro-inflammatory response. The inflammasome-mediated formation of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 involves the auto-proteolytic maturation of caspase-1. This study investigated if P. acnes activates inflammasomes. Propionibacterium acnes isolates (n = 29) with diverse origin were used as stimuli for peripheral leukocytes obtained from blood donors (BDs). The activity of inflammasomes was determined by measuring caspase-1 by flow cytometry and cytokine production by ELISA. A significant amount of caspase-1 was found in neutrophils upon P. acnes stimulation, whereas only a modest activation was seen in monocytes. The activation was mainly produced by components of the bacterial cell and no exo-products, because heat-killed and live bacteria caused high activation of caspase-1 as well as cytokine production, whereas the bacterial supernatant elicited minor effect. The response among different BDs varied significantly, almost fivefold. In addition, P. acnes of various origins showed considerable variation, however, the commensal isolates showed a stronger response compared with the invasive. In conclusion, although regarded as a harmless commensal of the skin, P. acnes strongly activates the inflammasome of human peripheral neutrophils.

  • 299.
    Saleeb, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mojica, Sergio
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Eriksson, Anna U.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C. David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis2018In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 1077-1089Article in journal (Refereed)
    Abstract [en]

    A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.

  • 300.
    Salzer, Jonatan
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Nyström, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Smoking as a risk factor for multiple sclerosis2013In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 19, no 8, p. 1022-1027Article in journal (Refereed)
    Abstract [en]

    Background: Smoking has been associated with an increased risk for multiple sclerosis, but no studies have measured levels of the nicotine metabolite cotinine in prospectively collected samples to assess exposure.

    Objective: To investigate the effects of laboratory defined tobacco use on the risk for multiple sclerosis using prospectively collected biobank blood samples.

    Methods: Levels of cotinine were measured in n=192 cases, and n=384 matched controls, using an immunoassay. The risk for multiple sclerosis was estimated using matched logistic regression.

    Results: Elevated cotinine levels (≥10 ng/ml) were associated with a significantly increased risk for multiple sclerosis, (odds ratio, OR 1.5, 95% confidence interval, CI 1.0–2.1). This association was only present in young individuals (below median age at blood sampling, <26.4 years), (OR 2.2, 95% CI 1.3–3.8).

    Conclusions: This study confirms that smoking is a risk factor for multiple sclerosis. It has the advantage of using analyses of cotinine levels in samples that were collected several years before disease onset, thus excluding any risk for recall bias and minimising the risk for reversed causation. Our results also suggest that the smoking related immunological events that contribute to the development of multiple sclerosis occur early in life.

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