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  • 1.
    Andersson, Ann-Catrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Venables, Patrick JW
    Tönjes, Ralf R
    Scherer, Jürgen
    Eriksson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Developmnental expression of HERV-R (ERV3) and HERV-K in human tissue2002In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 297, no 2, p. 220-225Article in journal (Refereed)
    Abstract [en]

    The human endogenous retroviruses (HERVs), ERV3 (HERV-R) and HERV-K, are both known to be transcriptionally active in human placenta. In the case of ERV3 there is also indirect evidence for its participation in cellular differentiation. In this study we examined the expression of ERV3 (HERV-R) and HERV-K in human normal fetal tissues by in situ hybridization. The highest level of ERV3 env expression was detected in primitive adrenal cortex. Elevated levels of expression were also found in the following developing tissues: kidneys (tubules), tongue, heart, liver, and central nervous system. Tissue-specific expression was found for HERV-K rec (former cORF) but not for pol/int transcripts. The highest rec expression was found in placenta and levels slightly higher than sense control were found in the rest of the tissues examined. Pol/Int was not possible to quantitate. It appears that ERV3 is expressed in an organ-specific way during embryogenesis and might suggest a possible role in the development and differentiation of human tissues.

  • 2. Andersson, Cecilia
    et al.
    Henriksson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Magnusson, Karl-Eric
    Nilsson, Mats
    Mirazimi, Ali
    In situ rolling circle amplification detection of Crimean Congo hemorrhagic fever virus (CCHFV) complementary and viral RNA2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 426, no 2, p. 87-92Article in journal (Refereed)
    Abstract [en]

    Crimean Congo hemorrhagic fever virus (CCHFV) is a human pathogen that causes a severe disease with high fatality rate for which there is currently no specific treatment. Knowledge regarding its replication cycle is also highly limited. In this study we developed an in situ technique for studying the different stages during the replication of CCHFV. By integrating reverse transcription, padlock probes, and rolling circle amplification, we were able to detect and differentiate between viral RNA (vRNA) and complementary RNA (cRNA) molecules, and to detect viral protein within the same cell. These data demonstrate that CCHFV nucleocapsid protein (NP) is detectable already at 6 hours post infection in vRNA- and cRNA-positive cells. Confocal microscopy showed that cRNA is enriched and co-localized to a large extent with NP in the perinuclear area, while vRNA has a more random distribution in the cytoplasm with only some co-localize with NP. However, vRNA and cRNA did not appear to co-localize directly. 

  • 3.
    Backström Winquist, Ellenor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Abdurahman, Samir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tranell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindström, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tingsborg, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schwartz, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inefficient splicing of segment 7 and 8 mRNAs is an inherent property of influenza virus A/Brevig Mission/1918/1 (H1N1) that causes elevated expression of NS1 protein2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 422, no 1, p. 46-58Article in journal (Refereed)
    Abstract [en]

    Influenza A virus encodes two segments (7 and 8) that produce mRNAs that can be spliced. We have investigated if naturally occurring sequence polymorphisms in the influenza A virus family affects splicing of these viral mRNAs, as that could potentially alter the NS1/NS2- and/or M1/M2-protein ratios. We compared splicing efficiency of segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) and A/Netherlands/178/95 (H3N2), as well as various H5N1 avian strains. Results revealed that both segment 7 and 8 mRNAs of A/Brevig Mission/1918/1 (H1N1) were inefficiently spliced compared to other influenza virus segment 7 and 8 mRNAs. This resulted in production of higher levels of functional NS1 protein, which could potentially contribute to the pathogenic properties of the A/Brevig Mission/1918/1 (H1N1). We also show that A/Brevig Mission/1918/1 (H1N1) segment 8 mRNAs responded differently to overexpression of SR proteins than A/Netherlands/178/95 (H3N2).

  • 4.
    Bergström Lind, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artemenko, Konstantin A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhao, Yanhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The phosphoproteome of the adenovirus type 2 virion2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 433, no 1, p. 253-261Article in journal (Refereed)
    Abstract [en]

    We have used a proteomics approach to identify sites of phosphorylation in the structural proteins of the Adenovirus type 2 particle. This protein modification might play an important role during infection. Peptides from highly purified virus were enriched for phosphorylations and analyzed by liquid chromatography-high-resolving mass spectrometry. Phosphorylations were identified in 11 structural peptides and 29 non-redundant phosphorylation sites were unambiguously assigned to specific amino acid. An unexpected result was the finding of phosphotyrosine in two of the viral polypeptides. The most highly phosphorylated protein was pIIIa with 12 identified phosphorylation sites. An identified preference for proline or leucine residue flanking the phosphorylation sites downstream suggests that cellular kinases are involved in many of the phosphorylations. Structural modeling showed that one site in the hexon is located on the outer side of the virus and could be of importance for the virus when attaching and entering cells.

  • 5.
    Granberg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zhao, Hongxing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Adenovirus-induced alterations in host cell gene expression prior to the onset of viral gene expression2006In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 353, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    In this report, we have studied gene expression profiles in human primary lung fibroblasts (IMR-90) during the very early phase of an adenovirus infection. Eight out of twelve genes with known functions encoded transcription factors linked to two major cellular processes; inhibition of cell growth (ATF3, ATF4, KLF4, KLF6 and ELK3) and immune response (NR4A1 and CEBPB), indicating that the earliest consequences of an adenovirus infection are growth arrest and induction of an immune response. A time course analysis showed that the induction of these immediate-early response genes was transient and suppressed after the onset of the adenovirus early gene expression.

  • 6. Hultcrantz, Monica
    et al.
    Hühn, Michael H.
    Wolf, Monika
    Olsson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Jacobson, Stella
    Williams, Bryan R.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Flodström-Tullberg, Malin
    Interferons induce an antiviral state in human pancreatic islet cells2007In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 367, no 1, p. 92-101Article in journal (Refereed)
    Abstract [en]

    Enterovirus infections, in particular those with Coxsackieviruses, have been linked to the development of type 1 diabetes (T1D). Although animal models have demonstrated that interferons (IFNs) regulate virus-induced T1D by acting directly on the beta cell, little is known on the human pancreatic islet response to IFNs. Here we show that human islet cells respond to IFNs by expressing signature genes of antiviral defense. We also demonstrate that they express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which induce type I IFN production in infected cells. Finally, we show for the first time that the IFN-induced antiviral state provides human islets with a powerful protection from the replication of Coxsackievirus. This may be critical for beta cell survival and protection from virus-induced T1D in humans.

  • 7.
    Inturi, Raviteja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kamel, Wael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Complementation of the human adenovirus type 5 VA RNAI defect by the Vaccinia virus E3L protein and serotype-specific VA RNAIs2015In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 485, p. 25-35Article in journal (Refereed)
    Abstract [en]

    Human adenoviruses (HAdVs) encode for multifunctional non-coding virus-associated (VA) RNAs, which function as powerful suppressors of the cellular interferon (IFN) and RNA interference (RNAi) systems. In this study we tested the ability of various plant and animal virus encoded RNAi and IFN suppressor proteins to functionally substitute for the HAdV-5 VA RNAI. Our results revealed that only the Vaccinia virus (VACV) E3L protein was able to substitute for the HAdV-5 VA RNAI functions in virus-infected cells. Interestingly, the E3L protein rescues the translational defect but does not stimulate viral capsid mRNA accumulation observed with VA RNA. We further show that the E3L C-terminal region containing the dsRNA-binding domain is needed to enhance VA RNAI mutant virus replication. Additionally, we show that the HAdV-4 and HAdV-37 VA RNAI are more effective than the HAdV-5 VA RNAI in rescuing virus replication.

  • 8. Johansson, Cecilia
    et al.
    Graham, Sheila V
    Dornan, Edward S
    Morgan, Iain M
    The human papillomavirus 16 E2 protein is stabilised in S phase.2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 394, no 2, p. 194-9Article in journal (Refereed)
    Abstract [en]

    The human papillomavirus 16 E2 protein regulates transcription from, and replication of, the viral genome and is also required for segregation of the viral genome via interaction with mitotic bodies. To regulate DNA replication E2 interacts with sequences around the origin of replication and recruits the viral helicase E1 via a protein-protein interaction, which then initiates viral genome replication. The replication role of E2 must originally function in a host cell S phase. In this report, we demonstrate that E2 is stabilised in the S phase of the cell cycle and that this stabilisation is accompanied by an increase in phosphorylation of the protein. This increased phosphorylation and stability are likely required for optimum viral DNA replication and therefore identification of the enzymes involved in regulating these properties of E2 will provide targets for therapeutic intervention in the viral life cycle. Preliminary studies have identified E2 as a Cdk2 substrate demonstrating this enzyme as a candidate kinase for mediating the in vivo phosphorylation of HPV16 E2.

  • 9.
    Källsten, Malin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Gromova, Arina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Zhao, Hongxing
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Beijer Lab, Rudbeck Lab.
    Valdés, Alberto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Konzer, Anne
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Beijer Lab, Rudbeck Lab.
    Lind, Sara Bergstrom
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Universitet.
    Temporal characterization of the non-structural Adenovirus type 2 proteome and phosphoproteome using high-resolving mass spectrometry2017In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 511, p. 240-248Article in journal (Refereed)
    Abstract [en]

    The proteome and phosphoproteome of non-structural proteins of Adenovirus type 2 (Ad2) were time resolved using a developed mass spectrometry approach. These proteins are expressed by the viral genome and important for the infection process, but not part of the virus particle. We unambiguously confirm the existence of 95% of the viral proteins predicted to be encoded by the viral genome. Most non-structural proteins peaked in expression at late time post infection. We identified 27 non-redundant sites of phosphorylation on seven different non-structural proteins. The most heavily phosphorylated protein was the DNA binding protein (DBP) with 15 different sites. The phosphorylation occupancy rate could be calculated and monitored with time post infection for 15 phosphorylated sites on various proteins. In the DBP, phosphorylations with time-dependent relation were observed. The findings show the complexity of the Ad2 non-structural proteins and opens up a discussion for potential new drug targets.

  • 10.
    Lind, Sara Bergström
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhao, Yanhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Post translational modifications in adenovirus type 22013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 447, no 1-2, p. 104-111Article in journal (Refereed)
    Abstract [en]

    We have combined 2-D SOS-PAGE with liquid chromatography-high resolving mass spectrometry (LC-MS) to explore the proteome of the adenovirus type 2 (Ad2) at the level of post translational modifications (PTMs). The experimental design included in-solution digestion, followed by titanium dioxide enrichment, as well as in-gel digestion of polypeptides after separation of Ad2 capsid proteins by 1-D and 2-D SOS-PAGE. All samples were analyzed using LC-MS with subsequent manual verification of PTM positions. The results revealed new phosphorylation sites that can explain the observed trains of protein spots observed for the pIII, pIIIa and ply proteins. The pin protein was found to be the most highly modified protein with now 18 verified sites of phosphorylation, three sites of nitrated tyrosine and one sulfated tyrosine. Nitrated tyrosines were also identified in pII. Lysine acetylations were detected in pII and pVI. The findings make the Ad2 virion much more complex than hitherto believed. 

  • 11.
    Mannervik, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fan, Shaoan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ström, Anne-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Helin, Kristian
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Adenovirus E4 open reading frame 4-induced dephosphorylation inhibits E1A activation of the E2 promoter and E2F-1-mediated transactivation independently of the retinoblastoma tumor suppressor protein1999In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 256, no 2, p. 313-321Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that the cell cycle-regulated E2F transcription factor is subjected to both positive and negative control by phosphorylation. Here we show that in transient transfection experiments, adenovirus E1A activation of the viral E2 promoter is abrogated by coexpression of the viral E4 open reading frame 4 (E4-ORF4) protein. This effect does not to require the retinoblastoma protein that previously has been shown to regulate E2F activity. The inhibitory activity of E4-ORF4 appears to be specific because E4-ORF4 had little effect on, for example, E4-ORF6/7 transactivation of the E2 promoter. We further show that the repressive effect of E4-ORF4 on E2 transcription works mainly through the E2F DNA-binding sites in the E2 promoter. In agreement with this, we find that E4-ORF4 inhibits E2F-1/DP-1-mediated transactivation. We also show that E4-ORF4 inhibits E2 mRNA expression during virus growth. E4-ORF4 has previously been shown to bind to and activate the cellular protein phosphatase 2A. The inhibitory effect of E4-ORF4 was relieved by okadaic acid, which inhibits protein phosphatase 2A activity, suggesting that E4-ORF4 represses E2 transcription by inducing transcription factor dephosphorylation. Interestingly, E4-ORF4 did not inhibit the transactivation capacity of a Gal4-E2F hybrid protein. Instead, E4-ORF4 expression appears to result in reduced stability of E2F/DNA complexes.

  • 12. Marincevic-Zuniga, Yanara
    et al.
    Gustavsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Multiply-primed rolling circle amplification of human papillomavirus using sequence-specific primers2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 432, no 1, p. 57-62Article in journal (Refereed)
    Abstract [en]

    Multiply-primed rolling circle amplification (RCA) is a suitable technique for amplification of circular templates and has been used to identify novel human papillomaviruses (HPV). In this study we develop an efficient RCA for whole genome amplification of HPV using HPV-specific primers in clinical samples and establish a protocol for whole genome sequencing using the Sanger method. Amplification of cloned HPV-genomes by RCA was compared using specific primers against random hexamers. Using HPV-specific primers increased the effectiveness on average 15.2 times and the enrichment of HPV relative to human gDNA on average 62.2 times, as compared to using random hexamer. RCA products were sequenced without need for cloning, even when using low-input amounts. The technique was successfully used on 4 patient samples from FTA cards, to generate whole HPV-genome sequences. Degenerated HPV-specific primers for RCA produce DNA of sufficient quality and quantity suitable for sequencing and other potential downstream analyses.

  • 13.
    Plevka, Pavel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Tars, Kaspars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Zeltins, Andris
    Balke, Ina
    Truve, Erkki
    Liljas, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    The three-dimensional structure of ryegrass mottle virus at 2.9 Å resolution2007In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 369, no 2, p. 364-374Article in journal (Refereed)
    Abstract [en]

    The crystal structure of the sobemovirus Ryegrass mottle virus (RGMoV) has been determined at 2.9 Å resolution. The coat protein has a canonical jellyroll β-sandwich fold. In comparison to other sobemoviruses the RGMoV coat protein is missing several residues in two of the loop regions. The first loop contributes to contacts between subunits around the quasi-threefold symmetry axis. The altered contact interface results in tilting of the subunits towards the quasi-threefold axis. The assembly of the T = 3 capsid of sobemoviruses is controlled by the N-termini of C subunits forming a so-called β-annulus. The other loop that is smaller in the RGMoV structure contains a helix that participates in stabilization of the β-annulus in other sobemoviruses. The loss of interaction between the RGMoV loop and the β-annulus has been compensated for by additional interactions between the N-terminal arms. As a consequence of these differences, the diameter of the RGMoV particle is 8 Å smaller than that of the other sobemoviruses.

    The interactions of coat proteins in sobemovirus capsids involve calcium ions. Depletion of calcium ions results in particle swelling, which is considered a first step in disassembly. We could not identify any density for metal ions in the proximity of the conserved residues normally involved in calcium binding, but the RGMoV structure does not show any signs of swelling. A likely reason is the low pH (3.0) of the crystallization buffer in which the groups interacting with the calcium ions are not charged.

  • 14.
    Somberg, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rush, Margaret
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fay, Joanna
    Ryan, Fergus
    Lambkin, Helen
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schwartz, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Adenovirus E4orf4 induces HPV-16 late L1 mRNA production2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 383, no 2, p. 279-290Article in journal (Refereed)
    Abstract [en]

    The adenovirus E4orf4 protein regulates the switch from early to late gene expression during the adenoviral replication cycle. Here we report that overexpression of adenovirus E4orf4 induces human papillomavirus type 16 (HPV-16) late gene expression from subgenomic expression plasmids. E4orf4 specifically overcomes the negative effects of two splicing silencers at the two late HPV-16 splice sites SD3632 and SA5639. This results in the production of HPV-16 spliced L1 mRNAs. We show that the interaction of E4orf4 with protein phosphatase 2A (PP2A) is necessary for induction of HPV-16 late gene expression. Also an E4orf4 mutant that fails to bind the cellular splicing factor ASF/SF2 fails to induce L1 mRNA production. Collectively, these results suggest that dephosphorylation of SR proteins by E4orf4 activates HPV-16 late gene expression. Indeed, a mutant ASF/SF2 protein in which the RS-domain had been deleted could itself induce HPV-16 late gene expression, whereas wild type ASF/SF2 could not.

  • 15. Trybala, E
    et al.
    Bergstrom, T
    Spillmann, Dorothe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svennerholm, B
    Olofsson, S
    Flynn, S
    Ryan, P
    Mode of Interaction Between Pseudorabies Virus and Heparan Sulfate/Heparin1996In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 218, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    It has been demonstrated that the efficient attachment of pseudorabies virus (PrV) is mediated by an interaction between glycoprotein C (gC) and a cellular heparin-like substance (T. C. Mettenleiter, L. Zsak, F. Zuckermann, N. Sugg, H. Kern, and T. Ben-Porat, J. Virol. 64, 278–286, 1990). According to the prevalent concept, this interaction is likely to occur between clusters of basic residues of PrV gC and the negatively charged sulfate esters and carboxylate groups of heparan sulfate/heparin. To elucidate which of the three major types of sulfate groups of heparan sulfate/heparin are involved in the interaction with PrV, we used selectively N-, 2-O-, and 6-O-desulfated samples and other modified heparins as competitors in virus-attachment assays. PrV exhibited limited preference for the specific sulfate groups of heparan sulfate/heparin in accordance with a hierarchy of 6-O- > 2-O- >N-sulfates. In addition, since selective removal of any of the specific sulfates had only a slight effect on the competition capacity of heparin, it is likely that the combination of any two of three types of sulfate groups could contribute to an interaction with PrV with an efficiency nearly equal to native, fully sulfated heparin. When tested on different cell lines the pattern of PrV requirement for the specificO-sulfate groups, i.e., 6-O-sulfates > 2-O-sulfates, remained the same. However, different minimum lengths of heparin fragments were required to inhibit PrV attachment to different cell lines, suggesting a relative virus flexibility in accommodation to different forms of heparan sulfate.

  • 16. Wille, Michelle
    et al.
    Tolf, Conny
    Avril, Alexis
    Latorre-Margalef, Neus
    Wallerstrom, Sofie
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Waldenstrom, Jonas
    Frequency and patterns of reassortment in natural influenza A virus infection in a reservoir host2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 443, no 1, p. 150-160Article in journal (Refereed)
    Abstract [en]

    Influenza A viruses (IAV) can dramatically alter both genotype and phenotype at a rapid rate as a product of co-infection and reassortment Avian IAV exhibit high levels of phylogenetic incongruence, suggesting high levels of reassortment in the virus reservoir. Using a natural-experimental system, we reconstructed relationships amongst 92 viruses across 15 subtypes from 10 Mallards in an autumn season. Phylogenetic analyses estimated that 56% of the isolated viruses were reassorted. Network analysis demonstrated different patterns of reassortment and limited exchange of segments between primary and secondary infections. No clear patterns of linkage between segments were found, and patterns within a season were likely the consequence of continued introduction of new constellations, high viral load and diversity in the wild bird reservoir, and co-infections. This is the first IAV study to implement multiple tools available for elucidating factors governing reassortment patterns in naturally infected Mallards.

  • 17.
    Wu, Cheng Jun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Öberg, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rashid, Asif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gupta, Rajesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mignardi, Marco
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A mouse mammary epithelial cell line permissive for highly efficient human adenovirus growth2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 435, no 2, p. 363-371Article in journal (Refereed)
    Abstract [en]

    Although a few immunocompetent animal models to study the immune response against human adenoviruses (HAdV) are available, such as Syrian hamsters and cotton rats, HAdV replication is several logs lower compared to human control cells. We have identified a non-transformed mouse epithelial cell line (NMuMG) where HAdV-2 gene expression and progeny formation was as efficient as in the highly permissive human A549 cells. HAdV from species, D and E (HAdV-37 and HAdV-4, respectively) also caused a rapid cytopathic effect in NMuMG cells, while HAdV from species A, B1, B2 and F (HAdV-12, HAdV-3, HAdV-11 and HAdV-41, respectively) failed to do so. NMuMG cells might therefore be useful in virotherapy research and the analysis of antiviral defense mechanisms and the determination of toxicity, biodistribution and specific antitumour activity of oncolytic HAdV vectors.

  • 18.
    Wu, Chengjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bai, Lufeng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Zhiqun
    Samuel, Charles E.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Poor growth of human adenovirus-12 compared to adenovirus-2 correlates with a failure to impair PKR activation during the late phase of infection2015In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 475, p. 120-128Article in journal (Refereed)
    Abstract [en]

    Human adenovirus type 12 (HAdV-12) displays a relatively low virulence and slow replication in cultured human cells, which is manifested by premature death of HAdV-12-infected cells. Whereas HAdV-2 induction of IFN-beta expression was transient, HAdV-12-infected cells maintained high levels of IFN-beta expression, protein kinase R (PKR) activation and eIF-2 alpha phosphorylation throughout the infectious cycle. The importance of the IFN-inducible PKR kinase in restriction of HAdV-12 was supported by the enhanced growth of the virus following PKR knockdown in HeLa cells. Ectopic expression of HAdV-2 VA RNAI increased HAdV-12 hexon protein expression, suggesting that insufficient VA RNA expression contributes to the restricted growth of HAdV-12. Although some adenovirus species are known to persist in human lymphoid tissues, HAdV12 has so far not been found. Thus, it is possible that the inability of HAdV12 to evade the INF response may have implications for the virus to establish long-lasting or persistent infections. (C) 2014 Elsevier Inc. All rights reserved.

  • 19.
    Wu, Chengjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lund Univ, Div Med Microbiol, S-22100 Lund, Sweden..
    Cao, Xiaofang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Huijbers, Elisabeth J. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Angiogenesis Lab, Amsterdam, Netherlands..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 489, p. 44-50Article in journal (Refereed)
    Abstract [en]

    Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver.

  • 20.
    Yin, Hong
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Medstrand, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kristofferson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dietrich, Ursula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åman, Pierre
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Characterization of human MMTV-like (HML) elements similar to a sequence that was highly expressed in a human breast cancer: further definition of the HML-6 group1999In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 256, no 1, p. 22-35Article in journal (Refereed)
    Abstract [en]

    Previously, we found a retroviral sequence, HML-6.2BC1, to be expressed at high levels in a multifocal ductal breast cancer from a 41-year-old woman who also developed ovarian carcinoma. The sequence of a human genomic clone (HML-6.28) selected by high-stringency hybridization with HML-6.2BC1 is reported here. It was 99% identical to HML-6.2BC1 and gave the same restriction fragments as total DNA. HML-6.28 is a 4.7-kb provirus with a 5'LTR, truncated in RT. Data from two similar genomic clones and sequences found in GenBank are also reported. Overlaps between them gave a rather complete picture of the HML-6.2BC1-like human endogenous retroviral elements. Work with somatic cell hybrids and FISH localized HML-6.28 to chromosome 6, band p21, close to the MHC region. The causal role of HML-6.28 in breast cancer remains unclear. Nevertheless, the ca. 20 Myr old HML-6 sequences enabled the definition of common and unique features of type A, B, and D (ABD) retroviruses. In Gag, HML-6 has no intervening sequences between matrix and capsid proteins, unlike extant exogenous ABD viruses, possibly an ancestral feature. Alignment of the dUTPase showed it to be present in all ABD viruses, but gave a phylogenetic tree different from trees made from other ABD genes, indicating a distinct phylogeny of dUTPase. A conserved 24-mer sequence in the amino terminus of some ABD envelope genes suggested a conserved function.

  • 21.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Activation of the interferon-induced STAT pathway during an adenovirus type 12 infection2009In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 392, no 2, p. 186-195Article in journal (Refereed)
    Abstract [en]

    We have previously described a temporal regulation of host cell gene expression during adenovirus type 2 infection (Ad2) of primary human fibroblasts. Among the eleven percent of genes deregulated by Ad2, a large fraction included genes involved in cell cycle, growth control and antiviral defense, consistent with the capacity of Ad2 to efficiently master the infected cell and cause an effectively productive infection. Adenovirus type 12 (Ad12), which belongs to the highly oncogenic subgroup, is characterised by slow progression, less cytopathic effect and lower virus yield compared to the non-oncogenic Ad2. Microarray analysis of host cell gene expression in Ad12 infected human lung fibroblasts (IMR90) demonstrated a quantitatively and qualitatively less impact on host cell gene expression, compared to Ad2. Of the relatively few genes up regulated during the course of Ad12 infection only two (5%) were identified as potential E2F targets, compared to the significant activation of E2F-dependent transcription observed during an Ad2 infection. Although approximately 30% of the genes deregulated by Ad12 were previously identified in Ad2-infected cells, a distinct difference was observed in a group of interferon-stimulated genes (ISGs). G1P2, IFI6, IFI16, IFIT1, IFIT2, IFITM1 and IRF9 were activated during the very late stage of infection, and a consistent induction of IFNbeta gene expression, preceding induction of the ISGs, was demonstrated by quantitative real-time PCR analysis. An activated JAK/STAT signalling pathway was also indicated by the accumulation of all components (STAT1, STAT2 and IRF9) of the ISGF3 transcription factor. Significantly, none of these ISGs was activated in Ad2 infected IMR90 cells. Thus, the inability of Ad12 to evade the interferon response might explain its restricted virulence.

  • 22.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Chen, Maoshan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    A new look at adenovirus splicing2014In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 456, p. 329-341Article in journal (Refereed)
    Abstract [en]

    Adenovirus type 2 RNA splicing events were quantitatively mapped by using deep cDNA sequencing. The majority of the previously identified splice sites were detected. The lack of complete consistency between the present and previous results is because of some sites which were incorrectly mapped in previous studies, such as the splice sites for pVII, pVIII and E3-11.6K. Several previously predicted splice sites such as that for E3-14.5K and E4ORF3/4 were not detected. In addition, several new splice sites were identified. The novel RNAs may code for hitherto undetected proteins or alternatively spliced mRNAs for known proteins. The open reading frames downstream of two novel splice sites, located in the major late transcription unit region, were shown to be highly conserved. Another interesting possibility is that some of them are non-coding RNAs. Finally, the adenovirus mRNA polyadenylation sites were accurately mapped and in some cases shown to be heterogeneous.

  • 23.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Chen, Maoshan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Identification of adenovirus-encoded small RNAs by deep RNA sequencing2013In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 442, no 2, p. 148-155Article in journal (Refereed)
    Abstract [en]

    Using deep RNA sequencing, we have studied the expression of adenovirus-encoded small RNAs at different times after infection. Nineteen small RNAs which comprised more than 1% of the total pool of small RNAs at least one time point were identified. These small RNAs were between 25 and 35 nucleotides long and mapped in the region of the VA RNAI and RNAII genes. However, the overlap was incomplete and some contained a few extra nucleotides at the 3' end. This finding together with the observation that some of the small RNAs were detected before VA RNA expression had started might indicate that they are derived from other precursors than VA RNAI and II. Interestingly, the small RNAs displayed different expression profiles during the course of the infection suggesting that they have different functions. An effort was made to identify their mRNA targets by using computer prediction and deep cDNA sequencing. The most significant targets for the earliest small RNAs were genes involved in signaling pathways. 

  • 24.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Chen, Maoshan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Fluctuating expression of microRNAs in adenovirus infected cells2015In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 478, p. 99-111Article in journal (Refereed)
    Abstract [en]

    The changes in cellular microRNA (miRNA) expression during the course of an adenovirus type 2 infection in human lung fibroblast were studied by deep RNA sequencing. Expressions of 175 miRNAs with over 100 transcripts per million nucleotides were changed more than 1.5-fold. The expression patterns of these miRNAs changed dramatically during the course of the infection, from upregulation of the miRNAs known as tumor suppressors (such as miR-22, miR-320, let-7, miR-181b, and miR-155) and down-regulation of oncogenic miRNAs (such as miR-21 and miR-31) early to downregulation of tumor suppressor miRNAs (such as let-7 family, mir-30 family, 23/27 cluster) and upregulation of oncogenic miRNAs (include miR-125, miR-27, miR-191) late after infection. The switch in miRNA expression pattern occurred when adenovirus DNA replication started. Furthermore, deregulation of cellular miRNA expression was a step-wise and special sets of miRNAs were deregulated in different phases of infection.

  • 25.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Chen, Moashan
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Distinct temporal changes in host cell lncRNA expression during the course of an adenovirus infection2016In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 492, p. 242-250Article in journal (Refereed)
    Abstract [en]

    The deregulation of cellular long non-coding RNA (lncRNA) expression during a human adenovirus infection was studied by deep sequencing. Expression of lncRNAs increased substantially following the progression of the infection. Among 645 significantly expressed lncRNAs, the expression of 398 was changed more than 2-fold. More than 80% of them were up-regulated and 80% of them were detected during the late phase. Eased on the genomic locations of the deregulated lncRNAs in relation to known mRNAs and miRNAs, they were predicted to be involved in growth, structure, apoptosis and wound healing in the early phase, cell proliferation in the intermediate phase and protein synthesis, modification and transport in the late phase. The most significant functions of cellular RNA-binding proteins, previously shown to interact with the deregulated lncRNAs identified here, are involved in RNA splicing, nuclear export and translation events. We hypothesize that adenoviruses exploit the lncRNA network to optimize their reproduction.

  • 26.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Dahlö, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    The transcriptome of the adenovirus infected cell2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 424, no 2, p. 115-128Article in journal (Refereed)
    Abstract [en]

    Alternations of cellular gene expression following an adenovirus type 2 infection of human primary cells were studied by using superior sensitive cDNA sequencing. In total, 3791 cellular genes were identified as differentially expressed more than 2-fold. Genes involved in DNA replication, RNA transcription and cell cycle regulation were very abundant among the up-regulated genes. On the other hand, genes involved in various signaling pathways including TGF-β, Rho, G-protein, Map kinase, STAT and NF-κB stood out among the down-regulated genes. Binding sites for E2F, ATF/CREB and AP2 were prevalent in the up-regulated genes, whereas binding sites for SRF and NF-κB were dominant among the down-regulated genes. It is evident that the adenovirus has gained a control of the host cell cycle, growth, immune response and apoptosis at 24h after infection. However, efforts from host cell to block the cell cycle progression and activate an antiviral response were also observed.

  • 27.
    Zhao, Hongxing
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    How adenovirus strives to control cellular gene expression2007In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 363, no 2, p. 357-375Article in journal (Refereed)
    Abstract [en]

    Host cell gene expression during the course of a human adenovirus infection in synchronized primary human lung fibroblasts was analyzed using cDNA microarrays. The slow progression of the infectious cycle in these cells allowed a detailed examination of cellular gene regulation. In total, 988 unique genes were identified as differentially expressed more than 2-fold. The cellular gene expression profiles closely correlated to the progression of the infection. Based on the observed expression patterns, the deregulation of cellular genes' expression could be separated into four periods: (i) the immediate response of the host to incoming virus; (ii) deregulation of cellular genes involved in cell cycle, growth control, and antiviral response; (iii) steady-state regulation of cellular gene expression during viral DNA replication; (iv) targeting of cellular genes involved in intra- and extra-cellular structure at the late phase of infection. The struggle of the virus to gain control of TGF-beta and Wnt signaling, as well as the apoptotic pathways, was conspicuous.

  • 28.
    Zhao, Xiaomin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fay, Joanna
    Lambkin, Helen
    Schwartz, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Identification of a 17-nucleotide splicing enhancer in HPV-16 L1 that counteracts the effect of multiple hnRNP A1-binding splicing silencers2007In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 369, no 2, p. 351-363Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus type 16 (HPV-16) infections can in rare cases persist and cause lesions that may progress to cervical cancer. Cells in the lesions are not permissive for virus production, nor are cervical cancer cells. The intracellular environment is such that it prevents production of the highly immunogenic, viral structural proteins L1 and L2. One may speculate that inhibition of L1 and L2 expression is a prerequisite for persistence and cancer progression. We have therefore investigated how expression of HPV-16 L1 is regulated. We found that the only splice site in the HPV-16 late region, which is used to produce L1 mRNAs, is under control of a splicing enhancer located in the 17 nucleotides immediately downstream of the splice site. However, the function of this enhancer in cervical cancer cells is largely overshadowed by multiple splicing silencers in the late region which bind to hnRNP A1. High levels of hnRNP A1 therefore inhibit HPV-16 L1 expression. Immunohistological analysis of cervical epithelia revealed that hnRNP A1 is expressed primarily in the lower layers of the epithelium. hnRNP A1 is undetectable in terminally differentiated cells that can express HPV-16 late genes, which supports the conclusion that high levels of hnRNP A1 inhibit HPV-16 L1 expression.

  • 29.
    Östberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Törmänen Persson, Heidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Akusjärvi, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Serine 192 in the tiny RS repeat of the adenoviral L4-33K splicing enhancer protein is essential for function and reorganization of the protein to the periphery of viral replication centers2012In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 433, no 2, p. 273-281Article in journal (Refereed)
    Abstract [en]

    The adenovirus L4-33K protein is a key regulator involved in the temporal shift from early to late pattern of mRNA expression from the adenovirus major late transcription unit. L4-33K is a virus-encoded alternative splicing factor, which enhances processing of 3’ splice sites with a weak sequence context. Here we show that L4-33K expressed from a transfected plasmid has a diffuse nuclear localization with strong enrichment in the nuclear membrane. We further show that the highly conserved part of the carboxy-terminal end of L4-33K, which functions as the splicing enhancer domain, is sufficient for nuclear localization of the protein. Interestingly, infection of the transfected cells caused a redistribution of L4-33K from the nuclear membrane into discrete ring-like structures corresponding to the viral transcription sites. We also show that serine 192 in the tiny RS repeat, which is critical for the splicing enhancer function of L4-33K, is necessary for the nuclear localization and redistribution of L4-33K protein into viral transcription sites. Collectively, our results show a good correlation between the activity of L4-33K as a splicing enhancer protein and its localization to viral transcription sites.

1 - 29 of 29
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