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  • 1.
    Asghar, Naveed
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro universitet.
    Lee, Yi-Ping
    Umeå universitet.
    Nilsson, Emma
    Umeå universitet.
    Lindqvist, Rickard
    Umeå universitet.
    Melik, Wessam
    Örebro universitet.
    Kröger, Andrea
    6Helmholtz Centre for Infection Research, Braunschweig, Germany / University of Magdeburg, Magdenbrug, Germany.
    Överby, Anna K.
    Umeå universitet.
    Johansson, Magnus
    Örebro universitet.
    The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, nr 6, artikkel-id 39265Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Torö-2003 with the wild-type (A)3C(A)6 sequence (Torö-6A) or with a modified (A)3C(A)38 sequence (Torö-38A). Torö-38A replicated poorly compared to Torö-6A in cell culture, but Torö-38A was more virulent than Torö-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.

  • 2.
    Asghar, Naveed
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Lindblom, Pontus
    Melik, Wessam
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Lindqvist, Richard
    Haglund, Mats
    Forsberg, Pia
    Overby, Anna K
    Andreassen, Ashild
    Lindgren, Per-Eric
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro University.
    Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance.2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 7, artikkel-id e103264Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3' non-coding region (3'NCR). A different genomic structure was found in the 3'NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3'NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A)3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A)3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the re-sequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

  • 3.
    Asghar, Naveed
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro universitet.
    Petersson, Mona
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Geografi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro univarsitet.
    Dinnétz, Patrik
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Miljövetenskap.
    Local land-scape effects on population dynamics of Ixodes ricinus2016Inngår i: Geospatial Health, ISSN 1827-1987, Vol. 11, s. 283-289, artikkel-id 487Artikkel i tidsskrift (Fagfellevurdert)
  • 4.
    Asghar, Naveed
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro universitet.
    Pettersson, John H-O
    Norwegian Institute of Public Health, Oslo, Norway / Statens veterinärmedicinska anstalt.
    Dinnétz, Patrik
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Miljövetenskap.
    Andreassen, Åshild
    Norwegian Institute of Public Health, Oslo, Norway.
    Johansson, Magnus
    Örebro universitet.
    Deep sequencing analysis of tick-borne encephalitis virus from questing ticks at natural foci reveals similarities between quasispecies pools of the virus2017Inngår i: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, nr 3, s. 413-421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Every year, tick-borne encephalitis virus (TBEV) causes severe central nervous system infection in 10 000 to 15 000 people in Europe and Asia. TBEV is maintained in the environment by an enzootic cycle that requires a tick vector and a vertebrate host, and the adaptation of TBEV to vertebrate and invertebrate environments is essential for TBEV persistence in nature. This adaptation is facilitated by the error-prone nature of the virus's RNA-dependent RNA polymerase, which generates genetically distinct virus variants called quasispecies. TBEV shows a focal geographical distribution pattern where each focus represents a TBEV hotspot. Here, we sequenced and characterized two TBEV genomes, JP-296 and JP-554, from questing Ixodes ricinus ticks at a TBEV focus in central Sweden. Phylogenetic analysis showed geographical clustering among the newly sequenced strains and three previously sequenced Scandinavian strains, Toro-2003, Saringe-2009 and Mandal-2009, which originated from the same ancestor. Among these five Scandinavian TBEV strains, only Mandal-2009 showed a large deletion within the 3' non-coding region (NCR), similar to the highly virulent TBEV strain Hypr. Deep sequencing of JP-296, JP-554 and Mandal-2009 revealed significantly high quasispecies diversity for JP-296 and JP-554, with intact 3' NCRs, compared to the low diversity in Mandal-2009, with a truncated 3' NCR. Single-nucleotide polymorphism analysis showed that 40% of the single-nucleotide polymorphisms were common between quasispecies populations of JP-296 and JP-554, indicating a putative mechanism for how TBEV persists and is maintained within its natural foci.

  • 5.
    Bertrand, Yann J.
    et al.
    Science and Historical Investigations of Evolution Laboratory of Dubá, Dubá, Czech Republic.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro University.
    Norberg, Peter
    Sahlgrenska University.
    Revisiting Recombination Signal in the Tick-Borne Encephalitis Virus: A Simulation Approach2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 10, artikkel-id e0164435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The hypothesis of wide spread reticulate evolution in Tick-Borne Encephalitis virus (TBEV) has recently gained momentum with several publications describing past recombination events involving various TBEV clades. Despite a large body of work, no consensus has yet emerged on TBEV evolutionary dynamics. Understanding the occurrence and frequency of recombination in TBEV bears significant impact on epidemiology, evolution, and vaccination with live vaccines. In this study, we investigated the possibility of detecting recombination events in TBEV by simulating recombinations at several locations on the virus' phylogenetic tree and for different lengths of recombining fragments. We derived estimations of rates of true and false positive for the detection of past recombination events for seven recombination detection algorithms. Our analytical framework can be applied to any investigation dealing with the difficult task of distinguishing genuine recombination signal from background noise. Our results suggest that the problem of false positives associated with low detection P-values in TBEV, is more insidious than generally acknowledged. We reappraised the recombination signals present in the empirical data, and showed that reliable signals could only be obtained in a few cases when highly genetically divergent strains were involved, whereas false positives were common among genetically similar strains. We thus conclude that recombination among wild-type TBEV strains may occur, which has potential implications for vaccination with live vaccines, but that these events are surprisingly rare.

  • 6.
    Bertrand, Yann
    et al.
    Göteborg University.
    Töpel, Mats
    Göteborg University.
    Elväng, Annelie
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa.
    First Dating of a Recombination Event in Mammalian Tick-Borne Flaviviruses2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 2, s. e31981-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.

  • 7.
    Broniarczyk, Justyna
    et al.
    Department of Molecular Virology, Adam Mickiewicz University.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    The NS1 protein of Influenza A virus targets human Scribble in asubtype specific mannerManuskript (preprint) (Annet vitenskapelig)
  • 8. Brooks, Andrew J
    et al.
    Johansson, Magnus
    Södertörns högskola, Avdelning Naturvetenskap.
    Criswell, Erin
    Jans, David A
    Vasudevan, Subhash G
    The Interdomain Region of Dengue NS5 ProteinInteracts with NS3 and Host Proteins2002Inngår i: Dengue Bulletin, ISSN 1020-895X, Vol. 26, s. 155-161Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Although dengue virus genome replication occurs in the cytoplasm of infected cells, it has been shown that the NS5 protein (RNA-dependent RNA polymerase) is hyperphosphorylated at a late stage in infection and localized to the cell nucleus. A 37 amino acid sequence of NS5 (residues 369-405) was shown to contain a functional nuclear localization signal (NLS) that interacted with the cellular nuclear transport factor, importin α/β heterodimer. Further studies using the yeast two-hybrid system revealed that the NS5 region (residues 320-368) immediately adjacent to the NLS contained an importin β-binding site that abuts or overlaps the binding site for the NS3 protein (protease/helicase). The importin β-binding site has also been shown to be a functional NLS (bNLS). Intriguingly, when both bNLS and NLS (residues 320-405) were present, the fused β -galactosidase protein did not accumulate in the nucleus. Here we provide a review of our studies on the NS5 interdomain region and compare it to other members of the Flavivirus genus in order to highlight the importance of this region as a possible target for developing broad-acting antiviral agent against dengue and other mechanistically-related viruses.

  • 9. Brooks, Andrew J
    et al.
    Johansson, Magnus
    James Cook University.
    John, Anna V
    Xu, Yibin
    Jans, David A
    Vasudevan, Subhash G
    The interdomain region of dengue NS5 protein that binds to the viral helicase NS3 contains independently functional importin beta 1 and importin alpha/beta-recognized nuclear localization signals.2002Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, nr 39, s. 36399-36407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dengue virus NS5 protein is a multifunctional RNA-dependent RNA polymerase that is essential for virus replication. We have shown previously that the 37- amino acid interdomain spacer sequence (residues (369)X(2)KKX(14)KKKX(11)RKX(3)405) of Dengue2 NS5 contains a functional nuclear localization signal (NLS). In this study, beta-galactosidase fusion proteins carrying point mutations of the positively charged residues or truncations of the interdomain linker region (residues 369-389 or residues 386-405) were analyzed for nuclear import and importin binding activities to show that the N-terminal part of the linker region (residues 369-389, a/bNLS) is critical for nuclear localization and is recognized with high affinity by the conventional NLS-binding importin alpha/beta heterodimeric nuclear import receptor. We also show that the importin beta-binding site (residues 320-368, bNLS) adjacent to the a/bNLS, previously identified by yeast two-hybrid analysis, is functional as an NLS, recognized with high affinity by importin beta, and able to target beta-galactosidase to the nucleus. Intriguingly, the bNLS is highly conserved among Dengue and related flaviviruses, implying a general role for the region and importin beta in the infectious cycle.

  • 10.
    Ellencrona, Ellen
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper.
    Melik, Wessam
    Södertörns högskola, Institutionen för livsvetenskaper.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper.
    Novel PDZ dependent cell associations of the NS5 proteins of Tick-borne encephalitis virus and West-Nile virusManuskript (preprint) (Annet vitenskapelig)
  • 11.
    Ellencrona, Karin
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper.
    Syed, Asim
    Södertörns högskola, Institutionen för livsvetenskaper.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism2009Inngår i: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 390, nr 4, s. 319-323Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dengue virus (DENV) and tick-borne encephalitis virus (TBEV) are flaviviruses, which can cause lethal hemorrhagic fever and encephalitis, respectively. Here, we demonstrate that the TBEV-NS5 and DENV-NS5 proteins use an internal binding mechanism to target human PDZ proteins. TBEV-NS5 has high affinity to regulating synaptic membrane exocytosis-2 (RIMS2) and Scribble, whereas DENV-NS5 binds primarily to the tight junction protein zonula occludens-1 (ZO-1). Targeting of TBEV-NS5 to the plasma membrane is stabilised by ZO-1; however, DENV-NS5 co-localises with ZO-1 in the nucleus. These interactions have potential important roles in the ability of flaviviruses to manipulate cell proliferation, junction permeability and the interferon pathways.

  • 12.
    Elväng, Annelie
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Bertrand, Yann
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Lönn, Mikael
    Södertörns högskola, Institutionen för livsvetenskaper, Biologi. Södertörns högskola, Institutionen för livsvetenskaper, Miljövetenskap.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa.
    Sequencing of a Tick-Borne Encephalitis Virus from Ixodes ricinus Reveals a Thermosensitive RNA Switch Significant for Virus Propagation in Ectothermic Arthropods.2011Inngår i: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 11, nr 6, s. 649-658Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is a flavivirus with major impact on global health. The geographical TBEV distribution is expanding, thus making it pivotal to further characterize the natural virus populations. In this study, we completed the earlier partial sequencing of a TBEV pulled out of a pool of RNA extracted from 115 ticks collected on Torö in the Stockholm archipelago. The total RNA was sufficient for all sequencing of a TBEV genome (Torö-2003), without conventional enrichment procedures such as cell culturing or suckling mice amplification. To our knowledge, this is the first time that the genome of TBEV has been sequenced directly from an arthropod reservoir. The Torö-2003 sequence has been characterized and compared with other TBE viruses. In silico analyses of secondary RNA structures formed by the two untranslated regions revealed a temperature-sensitive structural shift between a closed replicative form and an open AUG accessible form, analogous to a recently described bacterial thermoswitch. Additionally, novel phylogenetic conserved structures were identified in the variable part of the 3'-untranslated region, and their sequence and structure similarity when compared with earlier identified structures suggests an enhancing function on virus replication and translation. We propose that the thermo-switch mechanism may explain the low TBEV prevalence often observed in environmentally sampled ticks. Finally, we were able to detect variations that help in the understanding of virus adaptations to varied environmental temperatures and mammalian hosts through a comparative approach that compares RNA folding dynamics between strains with different mammalian cell passage histories.

  • 13. Hamsten, C.
    et al.
    Starkhammar, M.
    Tran, T. A. T.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro University.
    Bengtsson, U.
    Ahlen, G.
    Sallberg, M.
    Gronlund, H.
    van Hage, M.
    Identification of galactose-alpha-1,3-galactose in the gastrointestinal tract of the tick Ixode sricinus; possible relationship with red meat allergy2013Inngår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, nr 4, s. 549-552Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with IgE antibodies against the carbohydrate epitope galactose--1,3-galactose (-Gal) have reported severe allergic reactions after consumption of red meat. Investigations have revealed associations between IgE to -Gal and tick bites. We provide the first direct evidence that -Gal is present within ticks thus potentially explaining the relationship between tick exposure and sensitization to -Gal, with development of red meat allergy as a secondary phenomena. Serum from Swedish patients with delayed severe reactions to red meat was included in the study. A dose-dependent inhibition of IgE responses to -Gal by the tick Ixodesricinus is demonstrated. Furthermore, using cryostat-cut sections of I.ricinus, we show that both a monoclonal and a polyclonal antibody against -Gal stains the gastrointestinal tract of the tick. The same pattern is seen when staining with patient sera IgE positive to -Gal. These results confirm that the -Gal epitope is present in I.ricinus and imply host exposure to -Gal during a tick bite. This provides further evidence that tick bites are associated with IgE responses to -Gal and red meat allergy.

  • 14.
    Johansson, Magnus
    Södertörns högskola, Avdelning Naturvetenskap.
    Flavivirus: ett växande globalt hälsoproblem2003Inngår i: Teknik & vetenskap, ISSN 1402-5701, Vol. 19, nr 1, s. -46Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 15. Johansson, Magnus
    et al.
    Brooks, Andrew J
    Jans, David A
    Vasudevan, Subhash G
    A small region of the dengue virus-encoded RNA-dependent RNA polymerase, NS5, confers interaction with both the nuclear transport receptor importin-beta and the viral helicase, NS3.2001Inngår i: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 82, nr 4, s. 735-745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The dengue virus RNA-dependent RNA polymerase, NS5, and the protease/helicase, NS3, are multidomain proteins that have been shown to interact both in vivo and in vitro. A hyperphosphorylated form of NS5 that does not interact with NS3 has been detected in the nuclei of virus-infected cells, presumably as the result of the action of a functional nuclear localization sequence within the interdomain region of NS5 (residues 369-405). In this study, it is shown by using the yeast two-hybrid system that the C-terminal region of NS3 (residues 303-618) interacts with the N-terminal region of NS5 (residues 320-368). Further, it is shown that this same region of NS5 is also recognized by the cellular nuclear import receptor importin-beta. The interaction between NS5 and importin-beta and competition by NS3 with the latter for the same binding site on NS5 were confirmed by pull-down assays. The direct interaction of importin-beta with NS5 has implications for the mechanism by which this normally cytoplasmic protein may be targetted to the nucleus.

  • 16.
    Melik, Wessam
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Ellencrona, Karin
    Södertörns högskola, Institutionen för livsvetenskaper.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Elväng, Annelie
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Hedström, Chister
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Two PDZ binding motifs within NS5 have roles in Tick-borne encephalitis virus replication2012Inngår i: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 169, nr 1, s. 54-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The flavivirus genus includes important human pathogens like Tick-borne encephalitis virus (TBEV), Dengue virus (DV) and West-Nile virus (WNV), that can cause severe disease e.g. encephalitis or hemorrhagic fever. The NS5 protein is a multifunctional RNA dependent RNA polymerase indispensable for the flavivirus replication. We have previously shown that TBEVNS5 contains a unique internal PDZ binding motif (YS223) for specific targeting of the PDZ protein Scribble. This interaction has impact on both viral down regulation of host cellular defense systems and neurite outgrowth. Putative C-terminal PDZ binding motifs present in TBEVNS5 (-SII903) and WNVNS5 (-TVL905) have also previously been highlighted.

    To determine whether the PDZ binding motifs of TBEVNS5 has an effect on virus replication we constructed a DNA based sub-genomic TBEV replicon expressing firefly luciferase. The motifs within NS5 were mutated individually and in concert and the replicons were assayed in cell culture. Our results show that the replication rate was impaired in all mutants, which indicates that PDZ dependent host interactions influence flavivirus replication.We also find that the C-terminal PDZ binding motif present in TBEVNS5 and WNVNS5 are targeting various human PDZ domain proteins. TBEVNS5 has high affinity to Zonulaoccludens-2 (ZO-2),GIAP C-terminus interacting protein (GIPC), Calcium/calmodulin-dependent serine protein kinase (CASK) and Interleukin 16 (IL-16).A different pattern was observed for WNVNS5 as it associated with IL-16, and several other putative interaction partners.

  • 17.
    Melik, Wessam
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Nilsson, A S
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper.
    Detection strategies of tick-borne encephalitis virus in Swedish Ixodes ricinus reveal evolutionary characteristics of emerging tick-borne flaviviruses.2007Inngår i: Archives of Virology, ISSN 0304-8608, E-ISSN 1432-8798, Vol. 152, nr 5, s. 1027-1034Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The flaviviral tick-borne encephalitis virus (TBEV) is a human pathogen having significant impact on public health. The geographical distribution of TBEV and TBEV-like viruses is increasing, which makes it important to characterise the natural virus populations. Here we present four RT-PCR strategies designed for detection of broad types of tick-borne flaviviruses. Sequence information on more than 32% of a TBEV genome was generated from a small pool of ticks collected in the Stockholm archipelago on the island of Torö. The sequences were characterised and compared with those of other tick-borne flaviviruses, which classified the virus as Western European TBEV.

  • 18.
    Rytkönen, Paulina
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Måltidskunskap.
    Bonow, Madeleine
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Geografi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro universitet.
    Persson, Ylva
    Goat cheese production in Sweden - a pioneering experience in the re-emergence of local food2013Inngår i: Acta Agriculturae Scandinavica - Section B, ISSN 0906-4710, E-ISSN 1651-1913, Vol. 63, nr SI, s. 38-46Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The re-emergence and modernization of traditional goat-cheese production in Jamtland led to the articulation of a localized agri-food system that represents the frontline of the return and reinforcement of local food in Sweden. Already in the 1970s, some initiatives were undertaken to formalize the productive activities of this branch and to improve the product quality. The most important project was the articulation of a cooperative that, unlike all other Swedish cooperatives, engaged its members in the development of a joint trademark, development of a standardized assortment, common marketing efforts and finding creative solutions for infrastructure problems. Despite the overall success, we also found some downsides. Producing goat cheese requires that at least two people are involved, because the workload often leads to body injuries and illness for people working alone. By studying the institutional frameworks, rules and regulations, the economic function and entrepr! neurial dynamics, and the dynamics of knowledge and competences, the article highlights how and why farm dairies in Jamtland became reinforced and modernized. This grasps both the actions of individual economic agents and their interaction with their environment. A special emphasis was put on the role of regional authorities in this process. Even though many obstacles have been removed and the trade has found successful ways to solve strategic issues concerning product development and marketing, there are still important structural shortcomings that might decrease the profitability and endanger the future development of the trade. There is a lack of experience and infrastructure to solve more complex problems like animal healthand the potential risks related to the consumption of unpasteurized cheese and the increasing incidence of Tick-Borne Encephalitis (TBE).

  • 19. Vasudevan, Subhash G
    et al.
    Johansson, Magnus
    Brooks, Andrew J
    Llewellyn, Lyndon E
    Jans, David A
    Characterisation of inter- and intra-molecular interactions of the dengue virus RNA dependent RNA polymerase as potential drug targets.2001Inngår i: Il Farmaco, ISSN 0014-827X, E-ISSN 1879-0569, Vol. 56, nr 1-2, s. 33-36Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our research is directed towards enhancing the understanding of the molecular biology of dengue virus replication with the ultimate goal being to develop novel antiviral strategies based on preventing critical inter- or intra-molecular interactions required for the normal virus life cycle. The viral RNA-dependent RNA polymerase (NS5) and the viral helicase (NS3) interaction offers a possible target for inhibitors to bind and prevent replication. In this study the yeast-two hybrid system was used to show that a small region of NS5 interacts with NS3, and also with the cellular nuclear transport receptor importin-beta. Furthermore, intramolecular interaction between the two putative domains of NS5 can also be detected by the yeast two-hybrid assay. We have also modified the colony lift assay for the beta-galactosidase reporter activity in intact yeast cells which reflects the strength of interaction between two proteins to a microtiter plate format. This assay offers a unique opportunity to screen for small molecule compounds that block physiologically important interactions.

  • 20.
    Werme, Karin
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Wigerius, Michael
    Södertörns högskola, Institutionen för livsvetenskaper. Stockholm University.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper.
    Tick-borne encephalitis virus NS5 associates with membrane protein scribble and impairs interferon-stimulated JAK-STAT signalling.2008Inngår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, nr 3, s. 696-712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) NS5 protein is a multifunctional RNA-dependent RNA polymerase that is indispensable for viral replication. TBEV is considered to be highly neurovirulent and can cause lethal encephalitis. In this study, we demonstrate a novel interaction between TBEV NS5 and the PDZ protein scribble (hScrib) affecting interferon (IFN) type I and II mediated JAK-STAT signalling. The sequence of TBEV NS5 interacting with hScrib was identified using extensive site-directed mutagenesis analysis. Two consecutive mutations in the methyltransferase (MTase) domain of NS5 were found to disrupt binding to hScrib. Colocalization studies with hScrib demonstrated that TBEV NS5 was present at the plasma membrane of mammalian cells. To address the role of viral interference with the IFN response, NS5 proteins were expressed in IFN-stimulated cells. While TBEV NS5 substantially blocked phosphorylation of STAT1, a mutated NS5 protein defective in hScrib binding failed to inhibit JAK-STAT signalling correctly. Furthermore, hScrib knock-down resulted in re-localization of NS5 to intracellular locations and abrogated the impaired STAT1 phosphorylation. These results define the TBEV NS5 protein in concert with hScrib as an antagonist of the IFN response, by demonstrating a correlation between the association and JAK-STAT interference.

  • 21.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Dalhousie University.
    Asghar, Naveed
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för naturvetenskap, miljö och teknik, Biologi. Örebro university.
    Scribble controls NGF-mediated neurite outgrowth in PC12 cells2013Inngår i: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 92, nr 6-7, s. 213-221Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurite outgrowth is mediated by dynamic changes of the cytoskeleton and is largely controlled by Rho GTPases and their regulators. Here, we show that the polarity protein Scribble controls PC12 cell neurite outgrowth in response to nerve growth factor. Scribble knockdown decreases neurite numbers and increases neurite length. This effect is linked to TrkA the cognate receptor for NGF as pharmacological inhibition of phosphorylated TrkA (pTrkA) reduces Scribble expression. Moreover, Scribble forms a complex with the MAPK components ERK1/2 in a growth factor dependent manner. In RNAi experiments where Scribble expression is efficiently depleted sustained ERK1/2 phosphorylation is reduced. Conversely, siRNA with intermediate Scribble silencing efficiency fails to match this effect indicating that ERK1/2 activation depends on basic Scribble protein levels. Finally, Scribble translocates to the plasma membrane in response to growth factor where it complexes with HRas and Rac1 suggesting that the phenotype activated by loss of Scribble may be a result of altered GTPase activity. Together, these results demonstrate a novel role for Scribble in neurite outgrowth of PC12 cells.

  • 22.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa. Södertörns högskola, Institutionen för livsvetenskaper, Kemi.
    SCRIBBLE SCAFFOLDS KEY COMPONENTS IN NEURITE OUTGROWTHIMPLICATING DIRECT INVOLVEMENT IN CYTOSKELETON REGULATIONManuskript (preprint) (Annet vitenskapelig)
  • 23.
    Wigerius, Michael
    et al.
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Melik, Wessam
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Elväng, Annelie
    Södertörns högskola, Institutionen för livsvetenskaper, Molekylärbiologi.
    Johansson, Magnus
    Södertörns högskola, Institutionen för livsvetenskaper, Kemi. Södertörns högskola, Institutionen för livsvetenskaper, Internationell hälsa.
    Rac1 and Scribble are targets for the arrest of neurite outgrowth by TBE virus NS52010Inngår i: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 44, nr 3, s. 260-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) causes extensive CNS disease in humans known as TBE, however, relatively little is known of the molecular mechanisms for its progress. Here, we now show that TBEV produces defects in neuronal development of PC12 cells through a function of the viral NS5 protein. The methyltransferase domain of NS5 is critical and sufficient for restriction of nerve growth factor induced neurite outgrowth. This effect is reversed by expression of NS5 mutants unable to bind Scribble and unexpectedly, in Scribble depleted cells with binding-competent NS5. Furthermore, we also demonstrate that the Rho GTPase Rac1 and the guanine nucleotide-exchange factor, beta PIX are outcompeted by NS5 for binding to Scribble, linking to effects on neurite outgrowth by TBEV. Together, these findings provide the first experimental evidence that Rac1 and beta PIX are indirect targets of NS5 acting through the multifunctional polarity protein Scribble to oppose neuronal differentiation. In conclusion, our results offer a potential mechanism by which TBEV alters neuronal circuitry and opens new avenues for therapeutic interventions.

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