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  • 1.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Gunaltay, Sezin
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Tran, Pham Tue Hung
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Höglund, Urban
    Adlego Biomedical AB, Uppsala, Sweden.
    Johansson, Christer
    Academy of Quality Pharm Science and BiQ Pharma AB, Södertälje, Sweden.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sällberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    DNA launched suicidal flaviviruses as therapeutic vaccine candidates2018Conference paper (Refereed)
    Abstract [en]

    Chronic liver disease, resulting from Hepatitis B virus (HBV), Hepatitis D virus (HDV), or Hepatitis C virus (HCV) infections, contributes to a major health burden worldwide. The relativelyhigh cost of the HCV treatment brings concerns about the accessibility, especially in the developing countries. Hence, there exists a need for cost effect interventions with high efficiency. We aim to develop therapeutic vaccine candidates against HBV, HCV and HDV using DNA based subgenomic flavivirus replicons as a delivery system. Tick-borne encephalitis virus (TBEV), Langat virus (LGTV), West-Nile virus (WNV), or Kunjinvirus (KUNV) replicon with firefly luciferase geneas a reporter were expressed and characterized in cell culture studies. WNV and KUNV replicons showed significantly higher replication compared to their respective negative controls with unfunctional viral RNA dependent RNA polymerase. KUNV and WNV replicons were chosen for cloning the HCV or HB/DV vaccine candidate gene by replacing luciferasegene. Owing to the self-replicating trait of the flavivirus subgenomic replicons, Western blotting demonstrated that the antigen expression by KUNV and WNV replicons was several folds higher than the positive control. These results suggest that DNA based KUNV and WNV replicons may function as carriers for the hepatitis vaccine candidate genes, and these replicons are currently used for in vivostudies in animal models.

  • 2.
    Asghar, Naveed
    et al.
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden .
    Lee, Yi-Ping
    Department of Clinical Microbiology, Virology,Umeå University, Umeå, Sweden; The Laboratory for Molecular Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
    Nilsson, Emma
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden; The Laboratory for Molecular Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
    Lindqvist, Richard
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden; The Laboratory for Molecular Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Kröger, Andrea
    Innate Immunity and Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany; Institute for Microbiology, University of Magdeburg, Magdeburg, Germany.
    Överby, Anna K.
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden; The Laboratory for Molecular Medicine Sweden (MIMS), Umeå University, Umeå, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 39265Article in journal (Refereed)
    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.

  • 3.
    Asghar, Naveed
    et al.
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Lindblom, Pontus
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Melik, Wessam
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Lindqvist, Richard
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
    Haglund, Mats
    Department of Infectious Diseases, County Hospital, Kalmar, Sweden.
    Forsberg, Pia
    Division of Infectious Diseases, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Clinic of Infectious Diseases, Linköping University Hospital, Linköping, Sweden.
    Överby, Anna K.
    Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
    Andreassen, Åshild
    Division of Infectious Disease Control, Department of Virology, Norwegian Institute of Public Health, Oslo, Norway.
    Lindgren, Per-Eric
    Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Division of Medical Services, Department of Microbiology, County Hospital Ryhov, Jönköping, Sweden.
    Johansson, Magnus
    Örebro University, School of Medicine, Örebro University, Sweden. School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden; RiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Tick-Borne Encephalitis Virus Sequenced Directly from Questing and Blood-Feeding Ticks Reveals Quasispecies Variance2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e103264Article in journal (Refereed)
    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 resequenced 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.

  • 4.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Maravelia, Panagiota
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tarn, Hung
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Pasetto, Anna
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Frelin, Lars
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Höglund, Urban
    Johansson, Christer
    Sällberg, Matti
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Immunogenicity of DNA launched suicidal flavivirus replicons for protective vaccination against hepatitis viruses2019Conference paper (Refereed)
    Abstract [en]

    Chronic liver disease, resulting from Hepatitis B virus (HBV), Hepatitis D virus (HDV), or Hepatitis C virus (HCV) infections, contributes to a major health burden worldwide. Chronic infections with the hepatitis C virus (HCV) can be effectively cured by antivirals. However, as cured patients can be re-infected they lack protective immune responses. In addition, the relativelyhigh cost of the HCV treatment brings concerns about the accessibility, especially in the developing countries. Hence, there exists a need for cost effect vaccines with high efficiency to control and possibly eradicate Hepatitis viruses globally. The vaccine should induce either, or both, neutralizing antibodies and protective T cell responses. We therefore have developed DNA based flavivirus replicons as a potent delivery system that effectively prime HCV-specific T cell responses. We generated suicidal subgenomic DNA replicons of Tick-borne encephalitis virus (TBEV), Langat virus (LGTV), West-Nile virus (WNV), and Kunjinvirus (KUNV) expressing either a fusion protein between the HCV NS3/4A and a stork hepatitis B virus core or a vaccine candidate gene of HB/DV. Transfection experiments showed that the antigen expression by KUNV and WNV replicons was several folds higher than the antigen expression by standard DNA plasmid with CMV promoter. The immunogenicity of three suicidal flaviviral DNA replicons expressing HCV NS3/4A was tested in mice and compared to HCV NS3/4A expression by the standard DNA plasmid. The KUNV-HCV replicon was the best replicon-based immunogen with respect to priming of HCV NS3/4A-specific T cells as determined by ELISpot, dextramer staining, and polyfunctionality. Importantly, a mutant KUNV-HCV immunogen lacking replication failed to induce immune responses. Thus, the newly developed KUNV-based suicidal DNA launched replicon vaccine for HCV is a highly attractive candidate as a prophylactic vaccine against chronic hepatitis C. In addition, we are currently testing the immunogenicity of KUNV-HB/DV replicon in mice.

  • 5.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Tran, Pham Tue Hung
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Pasetto, Anna
    aboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Höglund, Urban
    Adlego Biomedical AB, Uppsala, Sweden.
    Johansson, Christer
    Academy of Quality Pharm Science and BiQ Pharma AB, Södertälje, Sweden.
    Sällberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Immunogenicity of DNA launched suicidal flavivirus replicons for protective vaccination against hepatitis viruses2019Conference paper (Refereed)
    Abstract [en]

    Chronic liver disease, resulting from Hepatitis B virus (HBV), Hepatitis D virus (HDV), or Hepatitis C virus (HCV) infections, contributes to a major health burden worldwide. Chronic infections with the hepatitis C virus (HCV) can be effectively cured by antivirals. However, as cured patients can be re-infected they lack protective immune responses. In addition, the relativelyhigh cost of the HCV treatment brings concerns about the accessibility, especially in the developing countries. Hence, there exists a need for cost effect vaccines with high efficiency to control and possibly eradicate Hepatitis viruses globally. The vaccine should induce either, or both, neutralizing antibodies and protective T cell responses. We therefore have developed DNA based flavivirus replicons as a potent delivery system that effectively prime HCV-specific T cell responses. We generated suicidal subgenomic DNA replicons of Tick-borne encephalitis virus (TBEV), Langat virus (LGTV), West-Nile virus (WNV), and Kunjinvirus (KUNV) expressing either a fusion protein between the HCV NS3/4A and a stork hepatitis B virus core or a vaccine candidate gene of HB/DV. Transfection experiments showed that the antigen expression by KUNV and WNV replicons was several folds higher than the antigen expression by standard DNA plasmid with CMV promoter. The immunogenicity of three suicidal flaviviral DNA replicons expressing HCV NS3/4A was tested in mice and compared to HCV NS3/4A expression by the standard DNA plasmid. The KUNV-HCV replicon was the best replicon-based immunogen with respect to priming of HCV NS3/4A-specific T cells as determined by ELISpot, dextramer staining, and polyfunctionality. Importantly, a mutant KUNV-HCV immunogen lacking replication failed to induce immune responses. Thus, the newly developed KUNV-based suicidal DNA launched replicon vaccine for HCV is a highly attractive candidate as a prophylactic vaccine against chronic hepatitis C. In addition, we are currently testing the immunogenicity of KUNV-HB/DV replicon in mice.

  • 6.
    Asghar, Naveed
    et al.
    Örebro University, School of Medical Sciences. School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden; iRiSC – Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Pettersson, John H-O
    Department of Infectious Disease Epidemiology and Modelling, Norwegian Institute of Public Health, Oslo, Norway; Department of Microbiology, National Veterinary Institute, Uppsala, Sweden; Department of Medical Biochemistry and Microbiology (IMBIM), Zoonosis Science Center, Uppsala University, Uppsala, Sweden.
    Dinnetz, Patrik
    School of Natural Science, Technology & Environmental Studies, Södertörn University, Huddinge, Sweden.
    Andreassen, Åshild
    Department of Virology, Division of Infectious Disease Control, Norwegian Institute of Public Health, Oslo, Norway.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Deep sequencing analysis of tick-borne encephalitis virus from questing ticks at natural foci reveals similarities between quasispecies pools of the virus2017In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, no 3, p. 413-421Article in journal (Refereed)
    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' RNA-dependent RNA polymerase that 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 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. SNP analysis showed that 40% of the SNPs 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.

  • 7.
    Asghar, Naveed
    et al.
    Södertörns Högskola, Huddinge, Sweden.
    Wessam, Melik
    Södertörns Högskola, Huddinge, Sweden.
    Lindblom, Pontus
    Linköpings Universitet, Linköping, Sweden.
    Lindgren, Per-Erik
    Linköpings Universitet, Linköping, Sweden.
    Andreassen, Åshild
    Norska folkhälsoinstitutet, Oslo, Norway.
    Johansson, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University, School of Medicine, Örebro University, Sweden.
    Genomic Sequencing of Tick-borne Encephalitis Virus frin Questing and Blood-Feeding Ixodes ricinus2013Conference paper (Other academic)
  • 8.
    Johansson, Magnus
    et al.
    Örebro University, School of Medical Sciences.
    Frelin, Lars
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Maravelia, Panagiota
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Asghar, Naveed
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Caro-Perez, Noelia
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Pasetto, Anna
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ahlen, Gustaf
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sallberg, Matti
    Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
    Immunogenicity of a New Flaviviral-Based DNA Launched Suicidal Replicon for Protective Vaccination Against Hepatitis C2019In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 27, no 4, p. 139-139Article in journal (Other academic)
  • 9.
    Tran, Pham Tue Hung
    et al.
    Örebro University, School of Medical Sciences.
    Asghar, Naveed
    Örebro University, School of Medical Sciences.
    Karlsson, Anders
    Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Nanoxis Consulting AB, Gothenburg, Sweden.
    Karlsson, Roger
    Department of Clinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Nanoxis Consulting AB, Gothenburg, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Screening of host proteins interacting with Kunjin, Langat, Zikareplication complex2019In: 16th Smögen Summer Symposium on Virology, 2019Conference paper (Refereed)
    Abstract [en]

    During infection and eclipse time, Flaviviruses induce invagination of the endoplasmic reticulum (ER) membrane to form compartments, protecting their viral replication complex. The rearrangements of ER membrane require modifications in ER membrane lipid constituents or binding of proteins to bend the membrane. Indeed, it has been implicated that both KUNV and DENV NS1, NS2A, NS4A, NS4B proteins could induce membrane remodelings. However, it is not well known whether host proteins can also participate in the formation and maintenance of these compartments.In this project, we aimed to identify host proteins interacting with Kunjin, Langat, Zika replication complex. These proteins may function for ER invagination during Flavivirus infection. We used human adenocarcinoma epithelial A549 cells as a cell model, mosquito-borne Zika, Kunjin virus, and tick-borne Langat virus as virus models. After virus infections, the ER membranes from infected and non-infected cells were harvested using ultracentrifuge with a sucrose gradient. Proteins from these ERs were identified using mass spectrometry. We compared the differences between the ER proteomes to identify host candidate proteins that can cause the RC formation. To narrows the list of true candidate proteins, we attempted to enrich the RC-containing fractions by doing co-immuno precipitation. We are doing TMT-MS to identify and quantify the host proteins from Co-IP elutions. The functions of these proteins will be characterized by using molecular techniques.

  • 10.
    Tran, Pham Tue Hung
    et al.
    Örebro University, School of Medical Sciences.
    Asghar, Naveed
    Örebro University, School of Medical Sciences.
    Karlsson, Roger
    Department ofClinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; NanoxisConsulting AB, Gothenburg, Sweden.
    Karlsson, Anders
    Department ofClinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; NanoxisConsulting AB, Gothenburg, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Identification and characterization of host proteins inducing the endoplasmic reticulum invagination during Flavivirus infection2019In: Positive-Strand RNA Viuses, 2019, p. 280-280Conference paper (Refereed)
    Abstract [en]

    When Flaviviruses infect host cells, they can induce invagination of endoplasmic reticulum (ER) membrane to form vesicle-like compartments. These unique structures are hypothetical to facilitate the viral replication by reducing diffusion of virus replication machinery and viral RNA, providing a scaffold to anchor the replication complex, and protecting viral RNA from host cell intrinsic surveillance. 

    The rearrangements of ER membrane to form these replication compartments (RCs) require modifications in its lipid constituents or binding of proteins to the membrane. Flaviviruses, indeed, use their proteins to generate RCs. It has been implicated that both KUNV and DENV viral NS1, NS2A, NS4A, NS4B proteins could induce membrane remodelings. However, it is recondite whether host proteins can also participate in the formation and maintenance of RCs.

    In this project, we aimed to identify and characterize of host proteins inducing RC generation during Flavivirus infections. We used A549 as a cell model, and mosquito-borne Zika and Kunjin virus, and tick-borne Langat virus as virus models. After virus infections, ER membranes were harvested using ultracentrifuge with a sucrose gradient. Proteins from these ERs were identified using mass spectrometry. We compared the differences between the ER proteomes of infected cells and non-infected cells to identify host candidate proteins that can cause the RC formation.  We are attempting to enrich the RC-containing fractions and identifying proteins here, which narrows the list of true candidate proteins. The candidate proteins then will be characterized by using molecular techniques such as gene knock down, overexpression, and microscopy techniques.

  • 11.
    Tran, Pham Tue Hung
    et al.
    Örebro University, School of Medical Sciences.
    Asghar, Naveed
    Örebro University, School of Medical Sciences.
    Karlsson, Roger
    Department ofClinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; NanoxisConsulting AB, Gothenburg, Sweden.
    Karlsson, Anders
    Department ofClinical Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden; NanoxisConsulting AB, Gothenburg, Sweden.
    Johansson, Magnus
    Örebro University, School of Medical Sciences.
    Melik, Wessam
    Örebro University, School of Medical Sciences.
    Screening of host proteins interacting with Kunjin, Langat, Zika replication complex2019In: Positive-Strand Rna Viuses, 2019Conference paper (Refereed)
    Abstract [en]

    When Flaviviruses infect host cells, they can induce invagination of endoplasmic reticulum (ER) membrane to form vesicle-like compartments. These unique structures are hypothetical to facilitate the viral replication by reducing diffusion of virus replication machinery and viral RNA, providing a scaffold to anchor the replication complex, and protecting viral RNA from host cell intrinsic surveillance. 

    The rearrangements of ER membrane to form these replication compartments (RCs) require modifications in its lipid constituents or binding of proteins to the membrane. Flaviviruses, indeed, use their proteins to generate RCs. It has been implicated that both KUNV and DENV viral NS1, NS2A, NS4A, NS4B proteins could induce membrane remodelings. However, it is recondite whether host proteins can also participate in the formation and maintenance of RCs.

    In this project, we aimed to identify and characterize of host proteins inducing RC generation during Flavivirus infections. We used A549 as a cell model, and mosquito-borne Zika and Kunjin virus, and tick-borne Langat virus as virus models. After virus infections, ER membranes were harvested using ultracentrifuge with a sucrose gradient. Proteins from these ERs were identified using mass spectrometry. We compared the differences between the ER proteomes of infected cells and non-infected cells to identify host candidate proteins that can cause the RC formation.  We are attempting to enrich the RC-containing fractions and identifying proteins here, which narrows the list of true candidate proteins. The candidate proteins then will be characterized by using molecular techniques such as gene knock down, overexpression, and microscopy techniques.

  • 12.
    Wigerius, Michael
    et al.
    Södertörn University, Huddinge, Sweden; Dalhousie University, Halifax, Canada.
    Asghar, Naveed
    Södertörn University, Huddinge, Sweden.
    Melik, Wessam
    Södertörn University, Huddinge, Sweden.
    Johansson, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Scribble controls NGF-mediated neurite outgrowth in PC12 cells2013In: European Journal of Cell Biology, ISSN 0171-9335, E-ISSN 1618-1298, Vol. 92, no 6-7, p. 213-221Article in journal (Refereed)
    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. (c) 2013 Elsevier GmbH. All rights reserved.

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