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  • 351. Toriola, Adetunji T.
    et al.
    Tolockiene, Egle
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schock, Helena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Surcel, Helja-Marja
    Zeleniuch-Jacquotte, Anne
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Free beta- human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer2014In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 10, no 3, p. 377-384Article in journal (Refereed)
    Abstract [en]

    Background: We investigated whether the free -human chorionic gonadotropin (free -hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. Materials & methods: Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. Results: The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49-1.27), free -hCG (hazard ratio: 0.85; 95% CI: 0.33-2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. Conclusion: In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free -hCG does not appear to provide any additional information.

  • 352.
    Trulsson, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Identifying target receptors for the short fiber knob of Human Adenovirus 40 and -412016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 353. Tuomisto, Jouko
    et al.
    Holl, Katsiaryna
    Rantakokko, Panu
    Koskela, Pentti
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Dillner, Joakim
    Ogmundsdottir, Helga M
    Vartiainen, Terttu
    Lehtinen, Matti
    Pukkala, Eero
    Maternal smoking during pregnancy and testicular cancer in the sons: A nested case-control study and a meta-analysis.2009In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, no 9, p. 1640-1648Article in journal (Refereed)
    Abstract [en]

    Some large ecological studies have noted a significant association of testicular cancer (TC) with maternal smoking during pregnancy, while several more controlled studies have been negative. It has been difficult to obtain reliable data on exposure because of the long lag time to cancer diagnosis. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal smoking in the risk of TC in the offspring. After reviewing the literature, we also performed a meta-analysis of published studies. For each index mother of the TC patient, three to nine matched control mothers with a cancer-free son born at the same time as the TC case were identified within each cohort. First trimester sera were retrieved from the 70 index mothers and 519 control mothers and were tested for cotinine level by a novel HPLC-MS-MS method developed. No statistically significant association between maternal cotinine level and risk of TC in the offspring was found (OR 0.68; 95% CI 0.35, 1.34). This is the first study based on individual exposure measurements. Its results agree with our meta-analysis of seven previous epidemiological studies (total number of 2149 cases, 2762 controls) using indirect exposure assessment (OR 1.0; 95% CI 0.88, 1.12).

  • 354.
    Upadhyay, Arunkumar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Viperin, a multifunctional radical SAM enzyme: biogenesis and antiviral mechanisms2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) is an interferon-induced antiviral protein. It has three distinct functional domains: the N-terminal domain, the radical SAM (S-adenosylmethionine) domain for binding iron-sulphur cluster, and the C-terminus domain. Viperin has a broad antiviral effect, and is also involved in the immune response signalling. However, the function and antiviral mechanism of viperin are still not well characterized. Thus the overall aim of the thesis was to investigate and better understand the function of viperin and its antiviral mechanism by identifying the cellular network of interaction partners. Affinity purification and mass spectrometry analysis were used to identify cellular proteins that interact with viperin.

    CIA1 (also known as CIAO1), a factor involved in loading of iron-sulphur (Fe/S) cluster was identified and confirmed to interact at the C-terminus of viperin. It was also seen that the C-terminal domain and the functional SAM domain of viperin was essential for loading the Fe/S cluster onto viperin. On a closer look at the biogenesis of viperin, we identified and confirmed viperin interaction with CIA2A, CIA2B, (also known as FAM96A and FAM96B respectively) and MMS19, which are other factors involved in the transfer of Fe/S clusters onto cytosolic Fe/S apo-proteins. Surprisingly, MMS19, which has been shown to act as an adapter protein for other Fe/S proteins, only interacted indirectly and was not required for transferring the Fe/S cluster. Similarly, the interaction of viperin with both the isoforms of CIA2 was interesting, but the role they play in viperin biogenesis and antiviral function is still not clear and requires further investigation.

    Study of the antiviral action of viperin against tick-borne encephalitis virus (TBEV) showed that the activity of the SAM domain is essential for the strong inhibition of genome replication of TBEV. Furthermore, viperin also affects the assembly and release of TBEV. Viperin interacts with GBF1 and downregulates its activity, thus preferentially inducing the secretion of viral capsid protein from the cell, and therefore disrupting the formation of infectious virus particles. The N-terminal domain of viperin is important for its effect on assembly and release.

    In summary, this work contributes to our general understanding of viperin biogenesis in the cell regarding the loading of Fe/S cluster onto viperin. It also addresses the importance of the different domains for its antiviral function against TBEV. Finally, mass spectrometry and viperin interactome analysis implicate many other interesting cellular pathways or processes that might give us a better understanding of viperin’s function and antiviral mechanism. 

  • 355.
    Upadhyay, Arunkumar S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Stehling, Oliver
    Hubel, Philipp
    Panayiotou, Christakis
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pichlmair, Andreas
    Rösser, Ralf
    Lill, Roland
    Överby, Anna
    Unusual iron-sulfur cluster maturation of the antiviral radical SAM protein viperinManuscript (preprint) (Other academic)
  • 356.
    Upadhyay, Arunkumar S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Stehling, Oliver
    Panayiotou, Christakis
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Roesser, Ralf
    Lill, Roland
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cellular requirements for iron-sulfur cluster insertion into the antiviral radical SAM protein viperin2017In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 33, p. 13879-13889Article in journal (Refereed)
    Abstract [en]

    Viperin (RSAD2) is an interferon-stimulated antiviral protein that belongs to the radical S-adenosylmethionine (SAM) enzyme family. Viperin's iron-sulfur (Fe/S) cluster is critical for its antiviral activity against many different viruses. CIA1 (CIAO1), an essential component of the cytosolic iron-sulfur protein assembly (CIA) machinery, is crucial for Fe/S cluster insertion into viperin and hence for viperin's antiviral activity. In the CIA pathway, CIA1 cooperates with CIA2A, CIA2B, and MMS19 targeting factors to form various complexes that mediate the dedicated maturation of specific Fe/S recipient proteins. To date, however, the mechanisms of how viperin acquires its radical SAM Fe/S cluster to gain antiviral activity are poorly understood. Using co-immunoprecipitation and Fe-55-radiolabeling experiments, we therefore studied the roles of CIA2A, CIA2B, and MMS19 for Fe/S cluster insertion. CIA2B and MMS19 physically interacted with the C terminus of viperin and used CIA1 as the primary viperin-interacting protein. In contrast, CIA2A bound to viperin's N terminus in a CIA1-, CIA2B-, and MMS19-independent fashion. Of note, the observed interaction of both CIA2 isoforms with a single Fe/S target protein is unprecedented in the CIA pathway. Fe-55-radiolabeling experiments with human cells depleted of CIA1, CIA2A, CIA2B, or MMS19 revealed that CIA1, but none of the other CIA factors, is predominantly required for (55F)e/S cluster incorporation into viperin. Collectively, viperin maturation represents a novel CIA pathway with a minimal requirement of the CIA-targeting factors and represents a new paradigm for the insertion of the Fe/S cofactor into a radical SAM protein.

  • 357.
    Upadhyay, Arunkumar S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pichlmair, Andreas
    Stehling, Oliver
    Bennett, Keiryn L.
    Dobler, Gerhard
    Guo, Ju-Tao
    Superti-Furga, Giulio
    Lill, Roland
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Department of Virology, University Freiburg, D-79008Freiburg, Germany.
    Weber, Friedemann
    Viperin is an iron-sulfur protein that inhibits genome synthesis of tick-borne encephalitis virus via radical SAM domain activity2014In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 16, no 6, p. 834-848Article in journal (Refereed)
    Abstract [en]

    Viperin is an interferon-induced protein with a broad antiviral activity. This evolutionary conserved protein contains a radical S-adenosyl-l-methionine (SAM) domain which has been shown in vitro to hold a [4Fe-4S] cluster. We identified tick-borne encephalitis virus (TBEV) as a novel target for which human viperin inhibits productionof the viral genome RNA. Wt viperin was found to require ER localization for full antiviral activity and to interact with the cytosolic Fe/S protein assembly factor CIAO1. Radiolabelling in vivo revealed incorporation of Fe-55, indicative for the presence of an Fe-S cluster. Mutation of the cysteine residues ligating the Fe-S cluster in the central radical SAM domain entirely abolished both antiviral activity and incorporation of Fe-55. Mutants lacking the extreme C-terminal W361 did not interact with CIAO1, were not matured, and were antivirally inactive. Moreover, intracellular removal of SAM by ectopic expression of the bacteriophage T3 SAMase abolished antiviral activity. Collectively, our data suggest that viperin requires CIAO1 for [4Fe-4S] cluster assembly, and acts through an enzymatic, Fe-S cluster- and SAM-dependent mechanism to inhibit viral RNA synthesis.

  • 358.
    Upadhyay, Arunkumar S.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Pichlmair, Andreas
    Stehling, Oliver
    Guo, Ju-Tao
    Lill, Roland
    Weber, Friedemann
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Viperin vs. tick-borne encephalitis virus: Mechanisms of a potent antiviral protein2013In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 63, no 3, p. 305-305Article in journal (Other academic)
  • 359. Verbruggen, Paul
    et al.
    Ruf, Marius
    Blakqori, Gjon
    Överby, Anna K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Heidemann, Martin
    Eick, Dirk
    Weber, Friedemann
    Interferon antagonist NSs of La Crosse virus triggers a DNA damage response-like degradation of transcribing RNA polymerase II2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 5, p. 3681-3692Article in journal (Refereed)
    Abstract [en]

    La Crosse encephalitis virus (LACV) is a mosquito-borne member of the negative-strand RNA virus family Bunyaviridae. We have previously shown that the virulence factor NSs of LACV is an efficient inhibitor of the antiviral type I interferon system. A recombinant virus unable to express NSs (rLACVdelNSs) strongly induced interferon transcription, whereas the corresponding wt virus (rLACV) suppressed it. Here, we show that interferon induction by rLACVdelNSs mainly occurs through the signaling pathway leading from the pattern recognition receptor RIG-I to the transcription factor IRF-3. NSs expressed by rLACV, however, acts downstream of IRF-3 by specifically blocking RNA polymerase II-dependent transcription. Further investigations revealed that NSs induces proteasomal degradation of the mammalian RNA polymerase II subunit RPB1. NSs thereby selectively targets RPB1 molecules of elongating RNA polymerase II complexes, the so-called IIo form. This phenotype has similarities to the cellular DNA damage response, and NSs was indeed found to transactivate the DNA damage response gene pak6. Moreover, NSs expressed by rLACV boosted serine 139 phosphorylation of histone H2A.X, one of the earliest cellular reactions to damaged DNA. However, other DNA damage response markers such as up-regulation and serine 15 phosphorylation of p53 or serine 1524 phosphorylation of BRCA1 were not triggered by LACV infection. Collectively, our data indicate that the strong suppression of interferon induction by LACV NSs is based on a shutdown of RNA polymerase II transcription and that NSs achieves this by exploiting parts of the cellular DNA damage response pathway to degrade IIo-borne RPB1 subunits.

  • 360.
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Viperin vs. tick-borne encephalitis virus: mechanism of a potent antiviral protein2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is a very important virus medically, causing mild or severe encephalitis often with long-lasting sequelae. Treatment of tick-borne encephalitis is limited to supportive care, and antiviral drugs are much needed.

    The type-I interferon (IFN) system is the first line of host defense against many viruses. Infected cells secrete type-I IFN to alert neighboring cells. These cells in turn upregulate the expression of antiviral proteins to protect themselves from the virus.

    In this work, we found that the interferon-induced host protein viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) has a pronounced antiviral effect against TBEV.

     

    Viperin is an evolutionarily conserved protein with three domains: the N-terminus, the radical S-adenosyl methionine (SAM) domain, and the C-terminus. Viperin shows antiviral activity against a broad spectrum of different viruses. However, its mode of action appears to be virus-specific.

    We therefore concentrated on determining the antiviral mechanism of viperin against TBEV. The specific questions addressed in this thesis are: (1) which steps of the TBEV infectious cycle are targeted by viperin?, (2) which domains of viperin are responsible for its antiviral activity?, and (3) which interaction partners does viperin need in order to have an antiviral effect against TBEV?

    First, we investigated which step(s) of the TBEV life cycle viperin targets by using several assays to examine the effects of viperin on virus binding, entry, genome replication, assembly, and release.

    We found that viperin inhibited the replication of positive-sense genomic RNA and also targeted particle release, selectively enhancing the release of membrane-associated capsid particles.

    For inhibition of genome replication, viperin was dependent on the host cellular protein CIAO1 (cytosolic iron-sulfur assembly component 1). CIAO1 interacted with the C-terminus of viperin and was necessary for the maturation and stability of viperin, and also for loading of an iron-sulfur cluster onto the SAM domain. The SAM domain required this iron-sulfur cluster to perform its function as a radical SAM enzyme, which was required for the inhibition of TBEV genome replication. In addition to the SAM domain and the C-terminus, viperin needed its N-terminus in order to be fully antivirally active during late replication, since the N-terminus directed viperin to the endoplasmic reticulum, where genome replication takes place.

    Furthermore, viperin targeted GBF1 (Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1), a host protein known to be involved in the secretory pathway. Interaction between the N-terminus of viperin and GBF1 appeared to induce an enhance release of capsid particles independently of the later steps of the classical secretory pathway. The enhanced secretion of capsid particles by viperin occurred at the expense of whole, infectious virions and is therefore a completely novel antiviral mechanism.

     

    In summary, this work identified viperin as a very strong inhibitor of TBEV, and its antiviral mechanism was characterized in detail. Viperin was found to target multiple steps in the TBEV infectious cycle by both inhibiting viral RNA replication and inducing secretion of capsid particles. These findings provide new insights into the interplay between TBEV and viperin, and offer new approaches to our understanding of the molecular and cellular mechanisms of TBEV infection, which may contribute to the development of a treatment for TBEV.

  • 361.
    Vonderstein, Kirstin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, E.
    Pasto, J.
    Nygård Skalman, L.
    Upadhyay, Arunkumar S.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hubel, P.
    Pichlmair, A.
    Lundmark, R.
    Överby, AK
    Viperin induces secretion of tick-borne encephalitis virus capsid particles by interacting with GBF1Manuscript (preprint) (Other academic)
  • 362.
    Vonderstein, Kirstin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hubel, Philipp
    Nygård Skalman, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Upadhyay, Arunkumar
    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).
    Pichlmair, Andreas
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Viperin targets flavivirus virulence by inducing assembly of non-infectious capsid particles2018In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 1, article id e01751-17Article in journal (Refereed)
    Abstract [en]

    Efficient antiviral immunity requires interference with virus replication at multiple layers targeting diverse steps in the viral life cycle. Here we describe a novel flavivirus inhibition mechanism that results in interferon-mediated obstruction of tick-borne encephalitis virus particle assembly, and involves release of malfunctional membrane associated capsid (C) particles. This mechanism is controlled by the activity of the interferon-induced protein viperin, a broad spectrum antiviral interferon stimulated gene. Through analysis of the viperin-interactome, we identified the Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1), as the cellular protein targeted by viperin. Viperin-induced antiviral activity as well as C-particle release was stimulated by GBF1 inhibition and knock down, and reduced by elevated levels of GBF1. Our results suggest that viperin targets flavivirus virulence by inducing the secretion of unproductive non-infectious virus particles, by a GBF1-dependent mechanism. This yet undescribed antiviral mechanism allows potential therapeutic intervention.Importance The interferon response can target viral infection on almost every level, however, very little is known about interference of flavivirus assembly. Here we show that interferon, through the action of viperin, can disturb assembly of tick-borne encephalitis virus. The viperin protein is highly induced after viral infection and exhibit broad-spectrum antiviral activity. However, the mechanism of action is still elusive and appear to vary between the different viruses, indicating that cellular targets utilized by several viruses might be involved. In this study we show that viperin induce capsid particle release by interacting and inhibiting the function of the cellular protein Golgi Brefeldin A resistant guanine nucleotide exchange factor 1 (GBF1). GBF1 is a key protein in the cellular secretory pathway and essential in the life cycle of many viruses, also targeted by viperin, implicating GBF1 as a novel putative drug target.

  • 363.
    Vågberg, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kumlin, Urban
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Humoral immune response to influenza vaccine in natalizumab-treated MS patients2012In: Neurological Research, ISSN 0161-6412, E-ISSN 1743-1328, Vol. 34, no 7, p. 730-733Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Natalizumab is a drug with documented efficacy in relapsing?remitting multiple sclerosis (RRMS). The mechanism of action of natalizumab has immunosuppressive properties and it is not yet investigated if treatment with natalizumab affects the immunological response to vaccination. This study aims to investigate the humoral immune response to influenza vaccine while undergoing treatment with natalizumab.

    METHODS: A cohort of 17 RRMS patients treated with natalizumab and 10 healthy controls received trivalent influenza A/B vaccine. Influenza-specific immunoglobulin G (IgG) levels were determined at baseline and after 4, 8, and 12 weeks.

    RESULTS: Both groups experienced a significant increase in anti-influenza B IgG after the vaccination. Both groups also experienced a smaller increase in anti-influenza A IgG, but this was only significant for the natalizumab group. The IgG titers compared between the groups did not differ significantly at any of the time points.

    DISCUSSION: These results indicate that vaccination against influenza in patients treated with natalizumab yields a humoral immune response comparable to that achieved in healthy individuals.

  • 364. Wang, Z H
    et al.
    Kjellberg, L
    Abdalla, H
    Wiklund, F
    Eklund, C
    Knekt, P
    Lehtinen, M
    Kallings, I
    Lenner, P
    Hallmans, G
    Mählck, C G
    Wadell, G
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Schiller, J
    Dillner, J
    Type specificity and significance of different isotypes of serum antibodies to human papillomavirus capsids.2000In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 181, no 2, p. 456-62Article in journal (Refereed)
    Abstract [en]

    Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and <25 samples contained IgG3 or IgM. Total IgG, IgA, and IgG1 were HPV type specific and were associated with HPV-16 DNA (odds ratios [ORs], 5.4, 5.0, and 5.9, respectively; P<.001) but not with other HPV DNA (ORs, 1.2, 1.2, and 0.8, respectively; P value was not significant). Total IgG and IgG1 were strongly associated with number of lifetime sex partners (P<.001); IgA was only associated with number of recent sex partners and lifetime sex partners among younger women. Total IgG, IgG1, and IgA were associated with cervical intraepithelial neoplasia type III and also predicted risk of future cervical neoplasia. IgG and IgG1 appeared to mark lifetime cumulative exposure, whereas IgA may mark recent or ongoing infection.

  • 365.
    Weber, Elvira
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Finsterbusch, Katja
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Lienenklaus, Stefan
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Gekara, Nelson O
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Janik, Dirk
    Institute of Pathology, Helmholtz Center Munich, Neuherberg, Germany.
    Weiss, Siegfried
    Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Kalinke, Ulrich
    Institute for Experimental Infection Research, TWINCORE, Hannover, Germany.
    Överby, Anna K
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kröger, Andrea
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
    Type I interferon protects mice from fatal neurotropic infection with Langat virus by systemic and local antiviral responses2014In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 89, no 21, p. 12202-12212Article in journal (Refereed)
    Abstract [en]

    Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of infections in humans. TBEV causes a broad range of pathological symptoms, ranging from meningitis to severe encephalitis or even hemorrhagic fever, with high mortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor deletions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE: The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne encephalitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are characterized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available. An improved understanding of antiviral innate immune responses is pivotal for the development of effective therapeutics. We show that type I IFN, an effector molecule of the innate immune system, is responsible for the extended survival of TBEV and Langat virus (LGTV), an attenuated member of the TBE serogroup. IFN production and signaling appeared to be essential in two different phases during infection. The first phase is in the periphery, by reducing systemic LGTV replication and spreading into the central nervous system (CNS). In the second phase, the local IFN response in the CNS prevents virus-induced inflammation and the development of encephalitis.

  • 366.
    Weber, Elvira
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Finsterbusch, Katja
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroger, Andrea
    Överby, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Type I interferon protects against lethal Langat virus infection2013In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 63, no 3, p. 308-308Article in journal (Other academic)
  • 367.
    Westerberg, Sonja
    et al.
    Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hagbom, Marie
    Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Rajan, Anandi
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Loitto, Vesa
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Persson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nordgren, Johan
    Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sharma, Sumit
    Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Magnusson, Karl-Eric
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Svensson, Lennart
    Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Medicine, Karolinska Institute, Stockholm, Sweden.
    Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells2018In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e00026-18Article in journal (Refereed)
    Abstract [en]

    Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.

  • 368.
    Wesula Lwande, Olivia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bucht, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    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.
    Inkoo virus: a common but unrecognized mosquito-borne virus in northern Europe2017In: Infectious Diseases HubArticle, review/survey (Other academic)
    Abstract [en]

    Inkoo virus (INKV) is a common but less explored mosquito-borne virus belonging to family Bunyaviridae, genus Orthobunyavirus of the California serogroup. The virus was originally isolated in Finland in 1964 and has since then been detected in other northern European countries including Norway, Russia and Sweden. The virus has been associated with fever and encephalitis, in addition, patients considered positive for INKV antibodies have been linked with neurologic disease.

  • 369.
    Wiklund, Tove
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Analysis of Alzheimer's disease markers in cells infected with Herpes simplex virus type 12016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 370.
    Wu, H. D.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Replication-competent adenovirus 11p vector armed with ADP gene at E1 region significantly improved tumour-killing effect on metastatic prostate cells in vitro and in vivo2017In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 28, no 12, p. A29-A29Article in journal (Other academic)
  • 371.
    Yanamandra, Kiran
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Alexeyev, Oleg
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zamotin, Vladimir
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Srivastava, Vaibhav
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Shchukarev, Andrey
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brorsson, Ann-Christin
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Tartaglia, Gian Gaetano
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Vogl, Thomas
    Institute of Immunology, University of Münster, Münster, Germany.
    Kayed, Rakez
    Department of Neurology, University of Texas Medical Branch, Galveston, Texas, United States of America.
    Wingsle, Gunnar
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dobson, Christopher M
    Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Morozova-Roche, Ludmilla A
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Amyloid formation by the pro-inflammatory S100A8/A9 proteins in the ageing prostate2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, p. e5562-Article in journal (Refereed)
    Abstract [en]

    Background The conversion of soluble peptides and proteins into polymeric amyloid structures is a hallmark of many age-related degenerative disorders, including Alzheimer's disease, type II diabetes and a variety of systemic amyloidoses. We report here that amyloid formation is linked to another major age-related phenomenon - prostate tissue remodelling in middle-aged and elderly men.

    Methodology/Principal Findings By using multidisciplinary analysis of corpora amylacea inclusions in prostate glands of patients diagnosed with prostate cancer we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. In prostate protease rich environment the amyloids are stabilized by dystrophic calcification and lateral thickening. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro under native and acidic conditions and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions.

    Conclusions/Significance These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate. The results provide strong support for the prediction that the generic ability of polypeptide chains to convert into amyloids could lead to their involvement in an increasing number of otherwise apparently unrelated diseases, particularly those associated with ageing.

  • 372. Zegenhagen, Loreen
    et al.
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Koniszewski, Nikolaus
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroeger, Andrea
    Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections2016In: Cytokine & growth factor reviews, ISSN 1359-6101, E-ISSN 1879-0305, Vol. 30, p. 95-101Article, review/survey (Refereed)
    Abstract [en]

    The central nervous system (CNS) is a highly complex organ with highly specialized cell subtypes. Viral infections often target specific structures of the brain and replicate in certain regions. Studies in mice deficient in type I Interferon (IFN) receptor or IFN-I3 have highlighted the importance of the type I IFN system against viral infections and non-viral autoimmune disorders in the CNS. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Increased efforts have been made to characterize IFN expression and responses in the brain. In this context, it is important to identify cells that produce IFN, decipher pathways leading to type I IFN expression and to characterize responding cells. In this review we give an overview about region specific aspects that influence local innate immune responses. The route of entry is critical, but also the susceptibility of different cell types, heterogeneity in subpopulations and micro-environmental cues play an important role in antiviral responses. Recent work has outlined the tremendous importance of type I IFNs, particularly in the limitation of viral spread within the CNS. This review will address recent advances in understanding the mechanisms of local type I IFN production and response, in the particular context of the CNS. 

  • 373. Zegenhagen, Loreen
    et al.
    Weber, Elvira
    Kurade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nair, Sharmila
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kroeger, Andrea
    Differential innate immune responses in various brain regions regulate antiviral response in the CNS during Tick-borne encephalitis virus infection2015In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 1, p. 91-91Article in journal (Other academic)
  • 374.
    Zhang, Lei-Qing
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Human adenovirus serotypes 4 and 11 show higher binding affinity and infectivity for endothelial and carcinoma cell lines than serotype 52003In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 84, no 3, p. 687-695Article in journal (Refereed)
    Abstract [en]

    Adenoviruses are promising vectors for human cancer gene therapy. However, the extensively used adenoviruses serotypes 2 and 5 (Ad2 and Ad5) from species C have a major disadvantage in being highly prevalent; thus, most adults have an immunity against the two viruses. Furthermore, the expression of coxsackievirus and adenovirus receptors for Ad2 and Ad5 varies in different cells. This study aims to identify adenovirus serotypes with specific tropism for endothelial cells and epithelial tumour cells. Comparison of the binding affinities of Ad31, Ad11, Ad5, Ad37, Ad4 and Ad41, belonging to species A-F, respectively, to established cell lines of hepatoma (HepG2), breast cancer (CAMA and MG7), prostatic cancer (DU145 and LNCaP) and laryngeal cancer (Hep2), as well as to endothelial cells (HMEC), was carried out by flow cytometric analysis. Ad11 from species B showed markedly higher binding affinity than Ad5 for the endothelial cell line and all carcinoma cell lines studied. Ad4 showed a specific binding affinity for hepatoma cells and laryneal carcinoma cells. The ability of Ad11, Ad4 and Ad5 to be expressed in hepatoma, breast cancer and endothelial cell lines was studied by immunostaining and (35)S-labelling of viral proteins in infected cells. Ad11 and Ad4 manifested a higher proportion of infected cells and a higher degree of hexon expression than Ad5.

  • 375. Zocher, Georg
    et al.
    Mistry, Nitesh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Frank, Martin
    Hähnlein-Schick, Irmgard
    Ekström, Jens-Ola
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Stehle, Thilo
    A sialic acid binding site in a human picornavirus2014In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 10, no 10, p. e1004401-Article in journal (Refereed)
    Abstract [en]

    The picornaviruses coxsackievirus A24 variant (CVA24v) and enterovirus 70 (EV70) cause continued outbreaks and pandemics of acute hemorrhagic conjunctivitis (AHC), a highly contagious eye disease against which neither vaccines nor antiviral drugs are currently available. Moreover, these viruses can cause symptoms in the cornea, upper respiratory tract, and neurological impairments such as acute flaccid paralysis. EV70 and CVA24v are both known to use 5-N-acetylneuraminic acid (Neu5Ac) for cell attachment, thus providing a putative link between the glycan receptor specificity and cell tropism and disease. We report the structures of an intact human picornavirus in complex with a range of glycans terminating in Neu5Ac. We determined the structure of the CVA24v to 1.40 angstrom resolution, screened different glycans bearing Neu5Ac for CVA24v binding, and structurally characterized interactions with candidate glycan receptors. Biochemical studies verified the relevance of the binding site and demonstrated a preference of CVA24v for alpha 2,6-linked glycans. This preference can be rationalized by molecular dynamics simulations that show that alpha 2,6-linked glycans can establish more contacts with the viral capsid. Our results form an excellent platform for the design of antiviral compounds to prevent AHC.

  • 376.
    Överby, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Det tidiga immunförsvaret nyckel i kampen mot TBE-virus2014In: Neurologi i Sverige, ISSN 2000-8538, Vol. 2, no 14, p. 68-74Article in journal (Other academic)
5678 351 - 376 of 376
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