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  • 1.
    Israelsson, Stina
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Ekström, Jens-Ola
    Department of Molecular Biology, Umeå University.
    Göransson, Anna
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Lindberg, A Michael
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences.
    Significance of an authentic 5´ genomic end for activation of viral replication using in vitro transcripts of echovirus 5 and its implication for the efficacy of oncolytic infectious nucleic acidManuscript (preprint) (Other academic)
  • 2.
    Israelsson, Stina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Sävneby, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Ekström, Jens-Ola
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science. Umeå universitet.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Improved replication efficiency of echovirus 5 after transfection of colon cancer cells using an authentic 5' RNA genome end methodology2014In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 32, no 6, p. 1063-1070Article in journal (Refereed)
    Abstract [en]

    Oncolytic virotherapy is a promising novel form of cancer treatment, but the therapeutic efficiency needs improvement. A potential strategy to enhance the therapeutic effect of oncolytic viruses is to use infectious nucleic acid as therapeutic agent to initiate an oncolytic infection, without administrating infectious viral particles. Here we demonstrate improved viral replication activation efficiency when transfecting cells with 5’ end authentic in vitro transcribed enterovirus RNA as compared to genomic RNA with additional non-genomic 5’ nucleotides generated by conventional cloning methods. We used echovirus 5 (E5) as an oncolytoc model virus due to its ability to replicate in and completely destroy five out of six colon cancer cell lines and kill artificial colon cancer tumors (HT29 spheroids), as shown here. An E5 infectious cDNA clone including a hammerhead ribozyme sequence was used to generate in vitro transcripts with native 5’ genome ends. In HT29 cells, activation of virus replication is approximately 20-fold more efficient for virus genome transcripts with native 5’ genome ends compared to E5 transcripts generated from a standard cDNA clone. This replication advantage remains when viral progeny release starts by cellular lysis 22 h post transfection. Hence, a native 5’ genomic end improves infection activation efficacy of infectious nucleic acid, potentially enhancing its therapeutic effect when used for cancer treatment. The clone design with a hammerhead ribozyme is likely to be applicable to a variety of oncolytic positive sense RNA viruses for the purpose of improving the efficacy of oncolytic virotherapy.

  • 3.
    Jonsson, Nina
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sävneby, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gullberg, Maria
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Evertsson, Kim
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Klingel, Karin
    University of Tübingen, Germany.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Efficient replication of recombinant Enterovirus B types, carrying different P1 genes in the coxsackievirus B5 replicative backbone2015In: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 50, no 3, p. 351-357Article in journal (Refereed)
    Abstract [en]

    Recombination is an important feature in theevolution of the Enterovirus genus. Phylogenetic studies ofenteroviruses have revealed that the capsid genomic region(P1) is type specific, while the parts of the genome codingfor the non-structural proteins (P2–P3) are species specific.Hence, the genome may be regarded as consisting of twomodules that evolve independently. In this study, it wasinvestigated whether the non-structural coding part of thegenome in one type could support replication of a virus witha P1 region from another type of the same species. A cas-sette vector (pCas) containing a full-length cDNA copy ofcoxsackievirus B5 (CVB5) was used as a replicative back-bone. The P1 region of pCas was replaced with the corre-sponding part from coxsackievirus B3Nancy(CVB3N),coxsackievirus B6Schmitt(CVB6S), and echovirus 7Wal-lace(E7W), all members of theEnterovirus Bspecies. Thereplication efficiency after transfection with clone-derivedin vitro transcribed RNA was studied and compared withthat of pCas. All the recombinant viruses replicated with similar efficiencies and showed threshold cycle (Ct) values,tissue culture infectivity dose 50 %, and plaque-forming unittiters comparable to viruses generated from the pCas con-struct. In addition to this, a clone without the P1 region wasalso constructed, and Western Blot and immunofluorescencestaining analysis showed that the viral genome could betranslated and replicated despite the lack of the structuralprotein-coding region. To conclude, the replicative back-bone of the CVB5 cassette vector supports replication ofintraspecies constructs with P1 regions derived from othermembers of theEnterovirus Bspecies. In addition to this,the replicative backbone can be both translated and repli-cated without the presence of a P1 region.

  • 4.
    Sävneby, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Reverse genetic studies of Enterovirus replication2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enteroviruses belong to the Picornaviridae family and are small icosahedral viruses with RNA genomes of positive polarity, containing a single open reading frame. They mostly cause mild or asymptomatic infections, but also a wide array of diseases including: poliomyelitis, encephalitis, gastroenteritis, aseptic meningitis, myocarditis, hand-foot-and-mouth disease, hepatitis and respiratory diseases, ranging from severe infections to the common cold. The projects described in this thesis have been carried out through reverse genetic studies of Enterovirus B and Rhinovirus C.

                      In Papers I and II, a cassette vector was used to study recombination and translation of the RNA genome. It was found that the non-structural coding region could replicate when combined with the structural protein-coding region of other viruses of the same species. Furthermore, the genome could be translated and replicated without the presence of the structural protein-coding region. Moreover, it was found that when two additional nucleotides were introduced, shifting the reading frame, the virus could revert to the original reading frame, restoring efficient replication. In Paper III, a vector containing the genome of echovirus 5 was altered to produce an authentic 5’end of the in vitro transcribed RNA, which increased efficiency of replication initiation 20 times. This result is important, as it may lead to more efficient oncolytic virotherapy. An authentic 5’end was further used in Paper IV, where replication of Rhinovirus C in cell lines was attempted. Although passaging of the virus was unsuccessful, the genome was replicated and cytopathic effect induced after transfection. The restriction of efficient replication was therefore hypothesized to lie in the attachment and entry stages of the replication cycle. In Paper V, a cytolytic virus was found to have almost 10 times larger impact on gene expression of the host cell than a non-cytolytic variant. Furthermore, the lytic virus was found to build up inside the host cell, while the non-cytolytic virus was efficiently released.

                      As a whole, this thesis has contributed to a deeper understanding of replication of enteroviruses, which may prove important in development of novel vaccines, antiviral agents and oncolytic virotherapies.

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  • 5.
    Sävneby, Anna
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Svensson, P. Andreas
    Linnaeus University, Faculty of Health and Life Sciences, Department of Biology and Environmental Science.
    Hafenstein, Susan
    The Pennsylvania State University College of Medicine, USA.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Virus derived from an Enterovirus B construct efficiently reverts from a frameshift mutation immediately beyond the translation initiation siteManuscript (preprint) (Other academic)
  • 6.
    Sävneby, Anna
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Luthman, Johannes
    Karolinska Institutet.
    Nordenskjold, Fabian
    Karolinska Institutet.
    Andersson, Björn
    Karolinska Institutet.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    The Transcriptome of Rhabdomyosarcoma Cells Infected with Cytolytic and Non-Cytolytic Variants of Coxsackievirus B2 Ohio-12016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164548Article in journal (Refereed)
    Abstract [en]

    The transcriptomes of cells infected with lytic and non-lytic variants of coxsackievirus B2 Ohio-1 (CVB2O) were analyzed using next generation sequencing. This approach was selected with the purpose of elucidating the effects of lytic and non-lytic viruses on host cell transcription. Total RNA was extracted from infected cells and sequenced. The resulting reads were subsequently mapped against the human and CVB2O genomes. The amount of intracellular RNA was measured, indicating lower proportions of human RNA in the cells infected with the lytic virus compared to the non-lytic virus after 48 hours. This may be explained by reduced activity of the cellular transcription/translation machinery in lytic enteroviral replication due to activities of the enteroviral proteases 2A and/or 3C. Furthermore, differential expression in the cells infected with the two virus variants was identified and a number of transcripts were singled out as possible answers to the question of how the viruses interact with the host cells, resulting in lytic or non-lytic infections.

  • 7.
    Sävneby, Anna
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Luthman, Johannes
    Karolinska institutet.
    Nordenskjöld, Fabian
    Karolinska institutet.
    Andersson, Björn
    Karolinska institutet.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Gene expression in rhabdomyosarcoma cells infected with cytolytic and non-cytolytic variants of coxsackievirus B2 OhioManuscript (preprint) (Other academic)
  • 8.
    Sävneby, Anna
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Lysholm, Fredrik
    Karolinska institutet ; Linköpings universitet.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Edman, Kjell
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Allander, Tobias
    Karolinska Institutet.
    Andersson, Björn
    Karolinska Institutet.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Restricted replication of the rhinovirus C34 prototype in standard cell linesManuscript (preprint) (Other academic)
  • 9.
    Turkki, Paula
    et al.
    Univ Jyvaskyla, Finland;Tampere Univ, Finland.
    Laajala, Mira
    Univ Jyvaskyla, Finland.
    Stark, Marie
    Univ Jyvaskyla, Finland.
    Vandesande, Helena
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sallinen-Dal Maso, Heidi
    Univ Jyvaskyla, Finland.
    Shroff, Sailee
    Univ Jyvaskyla, Finland.
    Sävneby, Anna
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Galitska, Ganna
    Univ Jyvaskyla, Finland.
    Lindberg, A. Michael
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Marjomaki, Varpu
    Univ Jyvaskyla, Finland.
    Slow Infection due to Lowering the Amount of Intact versus Empty Particles Is a Characteristic Feature of Coxsackievirus B5 Dictated by the Structural Proteins2019In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 93, no 20, p. 1-15, article id e01130-19Article in journal (Refereed)
    Abstract [en]

    Enterovirus B species typically cause a rapid cytolytic infection leading to efficient release of progeny viruses. However, they are also capable of persistent infections in tissues, which are suggested to contribute to severe chronic states such as myocardial inflammation and type 1 diabetes. In order to understand the factors contributing to differential infection strategies, we constructed a chimera by combining the capsid proteins from fast-cytolysis-causing echovirus 1 (EV1) with nonstructural proteins from coxsackievirus B5 (CVB5), which shows persistent infection in RD cells. The results showed that the chimera behaved similarly to parental EV1, leading to efficient cytolysis in both permissive A549 and semipermissive RD cells. In contrast to EV1 and the chimera, CVB5 replicated slowly in permissive cells and showed persistent infection in semipermissive cells. However, there was no difference in the efficiency of uptake of CVB5 in A549 or RD cells in comparison to the chimera or EV1. CVB5 batches constantly contained significant amounts of empty capsids, also in comparison to CVBS's close relative CVB3. During successive passaging of batches containing only intact CVB5, increasing amounts of empty and decreasing amounts of infective capsids were produced. Our results demonstrate that the increase in the amount of empty particles and the lowering of the amount of infective particles are dictated by the CVB5 structural proteins, leading to slowing down of the infection between passages. Furthermore, the key factor for persistent infection is the small amount of infective particles produced, not the high number of empty particles that accumulate. IMPORTANCE Enteroviruses cause several severe diseases, with lytic infections that lead to rapid cell death but also persistent infections that are more silent and lead to chronic states of infection. Our study compared a cytolytic echovirus 1 infection to persistent coxsackievirus B5 infection by making a chimera with the structural proteins of echovirus 1 and the nonstructural proteins of coxsackievirus B5. Coxsackievirus 85 infection was found to lead to the production of a high number of empty viruses (empty capsids) that do not contain genetic material and are unable to continue the infection. Coinciding with the high number of empty capsids, the amount of infective virions decreased. This characteristic property was not observed in the constructed chimera virus, suggesting that structural proteins are in charge of these phenomena. These results shed light on the mechanisms that may cause persistent infections. Understanding events leading to efficient or inefficient infections is essential in understanding virus-caused pathologies.

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